Heteroaryl compounds useful as inhibitors of e1 activating enzymes

ABSTRACT

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

PRIORITY CLAIM

This application is a Continuation of U.S. patent application Ser. No.11/890,338, filed Aug. 6, 2007, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/836,158, filed on Aug. 8,2006, which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compounds, compositions and methods for thetreatment of various disorders, particularly disorders of cellproliferation, including cancers, and inflammatory disorders. Inparticular, the invention provides compounds which inhibit the activityof E1 type activating enzymes.

BACKGROUND OF THE INVENTION

The post-translational modification of proteins by ubiquitin-likemolecules (ubls) is an important regulatory process within cells,playing key roles in controlling many biological processes includingcell division, cell signaling and the immune response. Ubls are smallproteins that are covalently attached to a lysine on a target proteinvia an isopeptide linkage with a C-terminal glycine of the ubl. Theubiquitin-like molecule alters the molecular surface of the targetprotein and can affect such properties as protein-protein interactions,enzymatic activity, stability and cellular localization of the target.

Ubiquitin and other ubls are activated by a specific E1 enzyme whichcatalyzes the formation of an acyl-adenylate intermediate with theC-terminal glycine of the ubl. The activated ubl molecule is thentransferred to the catalytic cysteine residue within the E1 enzymethrough formation of a thioester bond intermediate. The E1-ublintermediate and an E2 associate, resulting in a thioester exchangewherein the ubl is transferred to the active site cysteine of the E2.The ubl is then conjugated to the target protein, either directly or inconjunction with an E3 ligase, through isopeptide bond formation withthe amino group of a lysine side chain in the target protein.

The biological consequence of ubl modification depends on the target inquestion. Ubiquitin is the best characterized of the ubls and aconsequence of modification by ubiquitination is the degradation ofpoly-ubiquitinated proteins by the 26S proteasome. Ubiquitin isconjugated to its target proteins through an enzymatic cascade involvingits specific E1 activating enzyme, Uba1 (ubiquitin activating enzyme,UAE), a conjugating enzyme from the family of E2s, and a ubiquitinligase from either the RING or HECT classes of E3s. See, Huang et al.,Oncogene, 23:1958-71 (2004). Target specificity is controlled by theparticular combination of E2 and E3 protein, with >40 E2s and >100 E3sbeing known at present. In addition to ubiquitin, there are at least 10ubiquitin-like proteins, each believed to be activated by a specific E1activating enzyme and processed through similar but distinct downstreamconjugation pathways. Other ubls for which E1 activating enzymes havebeen identified include Nedd8 (APPBP1-Uba3), ISG15 (UBE1L) and the SUMOfamily (Aos1-Uba2).

The ubl Nedd8 is activated by the heterodimer Nedd8-activating enzyme(APPBP1-Uba3) (NAE) and is transferred to a single E2 (Ubc12),ultimately resulting in ligation to cullin proteins. The function ofneddylation is the activation of cullin-based ubiquitin ligases involvedin the ubiquitination and hence turnover of many cell cycle and cellsignaling proteins, including p27 and I-κB. See Pan et al., Oncogene.23:1985-97 (2004). The ubl SUMO is activated by the heterodimer sumoactivating enzyme (Aos1-Uba2) (SAE) and is transferred to a single E2(Ubc9), followed by coordination with multiple E3 ligases, ultimatelyresulting in sumoylation of target proteins. Sumo modification canaffect the cellular localization of target proteins and proteinsmodified by SUMO family members are involved in nuclear transport,signal transduction and the stress response. See Seeler and Dejean, NatRev Mol Cell Biol. 4:690-9, (2003). The function of sumoylation includesactivation of cell signaling pathways (e.g., cytokine, WNT, growthfactor, and steroid hormone signaling) involved in transcriptionregulation; as well as pathways involved in control of genomic integrity(e.g., DNA replication, response to DNA damage, recombination andrepair). See Muller et al, Oncogene. 23:1998-2006, (2004). There areother ubls (e.g., ISG15, FAT10, Apg12p) for which the biologicalfunctions are still under investigation.

A particular pathway of importance which is regulated via E1 activatingenzyme activities is the ubiquitin-proteasome pathway (UPP). Asdiscussed above, the enzymes UAE and NAE regulate the UPP at twodifferent steps in the ubiquitination cascade. UAE activates ubiquitinin the first step of the cascade, while NAE, via activation of Nedd8, isresponsible for the activation of the cullin based ligases, which inturn are required for the final transfer of ubiquitin to certain targetproteins A functional UPP pathway is required for normal cellmaintenance. The UPP plays a central role in the turnover of many keyregulatory proteins involved in transcription, cell cycle progressionand apoptosis, all of which are important in disease states, includingtumor cells. See, e.g., King et al., Science 274: 1652-1659 (1996);Vorhees et al., Clin. Cancer Res., 9: 6316-6325 (2003); and Adams etal., Nat. Rev. Cancer, 4: 349-360 (2004). Proliferating cells areparticularly sensitive to inhibition of the UPP. See, Drexler, Proc.Natl. Acad. Sci., USA 94: 855-860 (1977). The role of the UPP pathway inoncogenesis has led to the investigation of proteasome inhibition as apotential anticancer therapy. For example, modulation of the UPP pathwayby inhibition of the 26S proteasome by VELCADE® (bortezomib) has provento be an effective treatment in certain cancers and is approved for thetreatment of multiple myeloma and mantle cell lymphoma patients who havereceived at least one prior therapy. Examples of proteins whose levelsare controlled by cullin-based ubiquitin ligases which are downstream ofNAE and UAE activity include the CDK inhibitor p27^(Kip1) and theinhibitor of NFκB, IκB. See, Podust et al., Proc. Natl. Acad. Sci., 97:4579-4584 (2000), and Read et al., Mol. Cell Biol., 20: 2326-2333(2000). Inhibition of the degradation of p27 is expected to block theprogression of cells through the G1 and S phases of the cell cycle.Interfering with the degradation of IκB should prevent the nuclearlocalization of NF-κB, transcription of various NF-κB-dependent genesassociated with the malignant phenotype, and resistance to standardcytotoxic therapies. Additionally, NF-κB plays a key role in theexpression of a number of pro-inflammatory mediators, implicating a rolefor such inhibitors in inflammatory diseases. Furthermore, inhibition ofUPP has been implicated as a useful target for additional therapeutics,such as inflammatory disorders, including, e.g., rheumatoid arthritis,asthma, multiple sclerosis, psoriasis and reperfusion injury;neurodegenerative disorders, including e.g., Parkinson's disease,Alzheimer's disease, triplet repeat disorders; neuropathic pain;ischemic disorders, e.g., stroke, infarction, kidney disorders; andcachexia. See, e.g., Elliott and Ross, Am. J. Clin. Pathol., 116:637-46(2001); Elliott et al., J. Mol. Med., 81:235-45 (2003); Tarlac andStorey, J. Neurosci. Res. 74: 406-416 (2003); Mori et al., Neuropath.Appl. Neurobiol., 31: 53-61 (2005); Manning, Curr. Pain Headache Rep.,8: 192-8 (2004); Dawson and Dawson, Science, 302: 819-822 (2003); Kukan,J. Physiol. Pharmacol., 55: 3-15 (2004); Wojcik and DiNapoli, Stroke,35:1506-18 (2004); Lazarus et al., Am J Physiol., 27:E332-41 (1999).

Targeting E1 activating enzymes provides a unique opportunity tointerfere with a variety of biochemical pathways important formaintaining the integrity of cell division and cell signaling. E1activating enzymes function at the first step of ubl conjugationpathways; thus, inhibition of an E1 activating enzyme will specificallymodulate the downstream biological consequences of the ubl modification.As such, inhibition of these activating enzymes, and the resultantinhibition of downstream effects of ubl-conjugation, represents a methodof interfering with the integrity of cell division, cell signaling, andseveral aspects of cellular physiology which are important for diseasemechanisms. Thus, E1 enzymes such as UAE, NAE, and SAE, as regulators ofdiverse cellular functions, are potentially important therapeutictargets for the identification of novel approaches to treatment ofdiseases and disorders.

DESCRIPTION OF THE INVENTION

This invention provides compounds that are effective inhibitors of E1activating enzymes, particularly NAE. The compounds are useful forinhibiting E1 activity in vitro and in vivo, and are useful for thetreatment of disorders of cell proliferation, particularly cancers, andother disorders associated with E1 activity. Compounds of the inventionare of the general formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ring A is a 6-membered nitrogen-containing heteroaryl ring,        optionally fused to a 5- or 6-membered aryl, heteroaryl,        cycloaliphatic or heterocyclic ring, wherein either or both        rings is optionally substituted and one ring nitrogen atom is        optionally oxidized;    -   W is —CH₂—, —CHF—, —CF₂—, —CH(R¹)—, —CF(R¹)—, —NH—, —N(R¹)—,        —O—, —S—, or —NHC(O)—;    -   R is C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic; or R¹ is a C₂₋₄        alkylene chain that is attached to a ring position on Ring A to        form a 5-, 6-, or 7-membered fused ring, wherein the alkylene        chain optionally is substituted with C₁₋₄ aliphatic, C₁₋₄        fluoroaliphatic, ═O, —CN, or —C(O)N(R⁴)₂;    -   X is —CH₂—, —CHF—, —CF₂—, —NH—, or —O—;    -   Y is —O—, —S—, or —C(R^(m))(R^(n))—;    -   R^(a) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c) together form a bond;    -   R^(b) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(c) is selected from the group consisting of hydrogen, fluoro,        —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂,        —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or        C₁₋₄ fluoroaliphatic optionally substituted with one or two        substituents independently selected from the group consisting of        —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c) together form a bond;    -   R^(d) is selected from the group consisting of hydrogen, fluoro,        C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic;    -   R^(e) is hydrogen, or C₁₋₄ aliphatic; or R^(e), taken together        with one R^(f) and the intervening carbon atoms, forms a 3- to        6-membered spirocyclic ring; or R^(e), taken together with R^(m)        and the intervening carbon atoms, forms a fused cyclopropane        ring, which is optionally substituted with one or two        substituents independently selected from fluoro or C₁₋₄        aliphatic;    -   R^(e′) is hydrogen or C₁₋₄ aliphatic; or R^(e′), taken together        with R^(m) and the intervening carbon atoms, forms a fused        cyclopropane ring, which is optionally substituted with one or        two substituents independently selected from fluoro or C₁₋₄        aliphatic;    -   each R^(f) is independently hydrogen, fluoro, C₁₋₄ aliphatic, or        C₁₋₄ fluoroaliphatic; or two R^(f) taken together form ═O; or        two R^(f), taken together with the carbon atom to which they are        attached, form a 3- to 6-membered carbocyclic ring; or one        R^(f), taken together with R^(e) and the intervening carbon        atoms, forms a 3- to 6-membered spirocyclic ring;    -   R^(m) is hydrogen, fluoro, —N(R⁴)₂, or an optionally substituted        C₁₋₄ aliphatic group; or R^(m) and R^(n) together form ═O or        ═C(R⁵)₂; or R^(m) and R^(e), taken together with the intervening        carbon atoms, form a fused cyclopropane ring, which is        optionally substituted with one or two substituents        independently selected from fluoro or C₁₋₄ aliphatic; or R^(m)        and R^(e′), taken together with the intervening carbon atoms,        form a fused cyclopropane ring, which is optionally substituted        with one or two substituents independently selected from fluoro        or C₁₋₄ aliphatic;    -   R^(n) is hydrogen, fluoro, or an optionally substituted C₁₋₄        aliphatic group; or R^(m) and R^(n) together form ═O or ═C(R⁵)₂;    -   each R⁴ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on        the same nitrogen atom, taken together with the nitrogen atom,        form an optionally substituted 4- to 8-membered heterocyclyl        ring having, in addition to the nitrogen atom, 0-2 ring        heteroatoms independently selected from N, O, and S;    -   R^(4x) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted;    -   R^(4y) is hydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀        ar(C₁₋₄)alkyl, the aryl portion of which may be optionally        substituted, or an optionally substituted 5- or 6-membered aryl,        heteroaryl, or heterocyclyl ring; or    -   R^(4x) and R^(4y), taken together with the nitrogen atom to        which they are attached, form an optionally substituted 4- to        8-membered heterocyclyl ring having, in addition to the nitrogen        atom, 0-2 ring heteroatoms independently selected from N, O, and        S; and    -   each R⁵ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀        ar(C₁₋₄)alkyl;    -   each R⁶ independently is an optionally substituted aliphatic,        aryl, or heteroaryl group; and    -   m is 1, 2, or 3.

Compounds of the invention include those described generally above, andare further defined and illustrated by the detailed description andexamples herein.

As used herein, the term “E1,” “E1 enzyme,” or “E1 activating enzyme”refers to any one of a family of related ATP-dependent activatingenzymes involved in activating or promoting ubiquitin or ubiquitin-like(collectively “ubl”) conjugation to target molecules. E1 activatingenzymes function through an adenylation/thioester intermediate formationto transfer the appropriate ubl to the respective E2 conjugating enzymethrough a transthiolation reaction. The resulting activated ubl-E2promotes ultimate conjugation of the ubl to a target protein. A varietyof cellular proteins that play a role in cell signaling, cell cycle, andprotein turnover are substrates for ubl conjugation which is regulatedthrough E1 activating enzymes (e.g., NAE, UAE, SAE). Unless otherwiseindicated by context, the term “E1 enzyme” is meant to refer to any E1activating enzyme protein, including, without limitation, nedd8activating enzyme (NAE (APPBP1/Uba3)), ubiquitin activating enzyme (UAE(Uba1)), sumo activating enzyme (SAE (Aos1/Uba2)), or ISG15 activatingenzyme (Ube1L). Preferably, the term “E1 enzyme” refers to human NAE,SAE or UAE, and more preferably refers to NAE.

The term “E1 enzyme inhibitor” or “inhibitor of E1 enzyme” is used tosignify a compound having a structure as defined herein, which iscapable of interacting with an E1 enzyme and inhibiting its enzymaticactivity. Inhibiting E1 enzymatic activity means reducing the ability ofan E1 enzyme to activate ubiquitin like (ubl) conjugation to a substratepeptide or protein (e.g., ubiquitination, neddylation, sumoylation). Invarious embodiments, such reduction of E1 enzyme activity is at leastabout 50%, at least about 75%, at least about 90%, at least about 95%,or at least about 99%. In various embodiments, the concentration of E1enzyme inhibitor required to reduce an E1 enzymatic activity is lessthan about 1 μM, less than about 500 nM, less than about 100 nM, lessthan about 50 nM, or less than about 10 nM.

In some embodiments, such inhibition is selective, i.e., the E1 enzymeinhibitor reduces the ability of one or more E1 enzymes (e.g., NAE, UAE,or SAE) to promote ubl conjugation to substrate peptide or protein at aconcentration that is lower, preferably at least 2-fold, 5-fold,10-fold, 50-fold, or 100-fold lower, than the concentration of theinhibitor that is required to produce another, unrelated biologicaleffect. In some such embodiments, the E1 enzyme inhibitor reduces theactivity of one E1 enzyme at a concentration that is lower than theconcentration of the inhibitor that is required to reduce enzymaticactivity of a different E1 enzyme. In other embodiments, the E1 enzymeinhibitor also reduces the enzymatic activity of another E1 enzyme,preferably one that is implicated in regulation of pathways involved incancer (e.g., NAE and UAE).

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

The term “aliphatic”, as used herein, means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation, but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof, such as cycloalkyl, (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)-alkenyl. In various embodiments, thealiphatic group has one to ten, one to eight, one to six, one to four,or one, two, or three carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from one to twelve carbon atoms. For purposes of the presentinvention, the term “alkyl” will be used when the carbon atom attachingthe aliphatic group to the rest of the molecule is a saturated carbonatom. However, an alkyl group may include unsaturation at other carbonatoms. Thus, alkyl groups include, without limitation, methyl, ethyl,propyl, allyl, propargyl, butyl, pentyl, and hexyl. The term “alkoxy”refers to an —O-alkyl radical.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on a cycloaliphatic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings, where the radical or point of attachment is on thealiphatic ring. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro. Nonlimiting examples of fluoroaliphatics include —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CF₂CH₃, and —CF₂CF₃.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on an arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 t electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Thus, when used in reference to a ring atom of a heteroaryl,the term “nitrogen” includes an oxidized nitrogen (as in pyridineN-oxide). Certain nitrogen atoms of 5-membered heteroaryl groups alsoare substitutable, as further defined below. Heteroaryl groups include,without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.

In some embodiments, two adjacent substituents on a heteroaryl ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring”, or “heteroaryl group”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “aromatic ring” and “aromatic ring system”refer to an optionally substituted mono-, bi-, or tricyclic group having0-6, preferably 0-4 ring heteroatoms, and having 6, 10, or 14 πelectrons shared in a cyclic array. Thus, the terms “aromatic ring” and“aromatic ring system” encompass both aryl and heteroaryl groups.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain which is optionallysubstituted.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from one to six, from one to four, from oneto three, from one to two, or from two to three. A substituted alkylenechain is a polymethylene group in which one or more methylene hydrogenatoms is replaced with a substituent. Suitable substituents includethose described below for a substituted aliphatic group. An alkylenechain also may be substituted at one or more positions with an aliphaticgroup or a substituted aliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R*)═C(R*)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R*)—, —N(R⁺)CO—,—N(R⁺)C(O)N(R⁺)—, —N(R⁺)CO₂—, —C(O)N(R⁺)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —OC(O)N(R⁺)—, —C(NR⁺)═N, —C(OR*)═N—, —N(R⁺)—N(R⁺)—,or —N(R⁺)S(O)₂—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a five to eight membered aromatic or non-aromatic ring having, inaddition to the nitrogen atom, zero to two ring heteroatoms selectedfrom N, O, and S. Each R* independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with—O-include —CH₂OCH₂—, —CH₂O(CH₂)₂—, —CH₂O(CH₂)₃—, —CH₂O(CH₂)₄—,—(CH₂)₂OCH₂—, —(CH₂)₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—, —(CH₂)₃O(CH₂)—,—(CH₂)₃O(CH₂)₂—, and —(CH₂)₄O(CH₂)—. Other examples of alkylene chainsthat are “interrupted” with functional groups include —CH₂GCH₂—,—CH₂G(CH₂)₂—, —CH₂G(CH₂)₃—, —CH₂G(CH₂)₄—, —(CH₂)₂GCH₂—, —(CH₂)₂G(CH₂)₂—,—(CH₂)₂G(CH₂)₃—, —(CH₂)₃G(CH₂)—, —(CH₂)₃G(CH₂)₂—, and —(CH₂)₄G(CH₂)—,wherein G is one of the “interrupting” functional groups listed above.

For purposes of clarity, all bivalent groups described herein,including, e.g., the alkylene chain linkers described above and thevariables D, E, F, G, Q, U, W, Y, V¹, T¹, T², T³, and T⁴ are intended tobe read from left to right, with a corresponding left-to-right readingof the formula or structure in which the variable appears. When thebivalent group is contained within a ring, a left-to-right reading ofthe variable corresponds to a clockwise reading of the ring structure inwhich the variable appears.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention. A stable or chemically feasible compound is one inwhich the chemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., preferably from about−20° C. to about +40° C., in the absence of moisture or other chemicallyreactive conditions, for at least a week, or a compound which maintainsits integrity long enough to be useful for therapeutic or prophylacticadministration to a patient.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The term “substitutable”, when used inreference to a designated atom, means that attached to the atom is ahydrogen radical, which can be replaced with the radical of a suitablesubstituent.

The phrase “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and thesubstituents may be either the same or different. As used herein, theterm “independently selected” means that the same or different valuesmay be selected for multiple instances of a given variable in a singlecompound.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂, —NR⁺CO₂R^(o),—O—CO₂R^(o), —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*, —C(O)R*,—C(O)N(R⁺)₂, —C(O)N(R⁺)OR*, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—N(R⁺)₂,—C(═NR⁺)—N(R⁺)—OR*, —C(═NR⁺)—OR*, —C(R^(o))═N—OR*, —N(R⁺)—N(R⁺)₂,—N(R⁺)OR*, —N(R⁺) C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*,—N(R⁺)C(═NR⁺)—R^(o), —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂, —P(O)(R*)₂,—P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) is anoptionally substituted aliphatic or aryl group, and R⁺ and R* are asdefined above, or two adjacent substituents, taken together with theirintervening atoms, form a 5- to 6-membered unsaturated or partiallyunsaturated ring having 0-3 ring atoms selected from the groupconsisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R⁺)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where ═ represents a doublebond, and each R* and R^(o) is as defined above. One of ordinary skillin the art will recognize that substituents that are attached by way ofa double bond requires replacement of two hydrogen radicals on thesubstitutable carbon atom. For the purposes of clarity, the term“substituted aliphatic” refers to an aliphatic group having at least onenon-aliphatic substituent.

Suitable substituents on a substitutable nitrogen atom of a heteroarylor heterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R^(o),—C(O)—C(O)R*, —C(O)CH₂C(O)R*, —SO₂R^(o), —SO₂N(R*)₂, —C(═S)N(R*)₂,—C(═NH)—N(R*)₂, and —NR*SO₂R^(o); wherein each R* and R^(o) is asdefined above.

Unless otherwise stated, structures depicted herein are meant to includecompounds which differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structureexcept for the replacement of a hydrogen atom by a deuterium or tritium,or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon arewithin the scope of the invention.

It also will be apparent to one skilled in the art that certaincompounds of this invention may exist in tautomeric forms, all suchtautomeric forms of the compounds being within the scope of theinvention. Unless stereochemical configuration is expressly defined,structures depicted herein are meant to include all stereochemical formsof the structure; i.e., the R and S configurations for each asymmetriccenter. Therefore, unless otherwise indicated, single stereochemicalisomers as well as enantiomeric and diastereomeric mixtures of thepresent compounds are within the scope of the invention. By way ofexample, the compounds of formula (I) wherein R^(a) is hydroxy can haveR or S configuration at the carbon atom bearing R^(a). Both the R andthe S stereochemical isomers, as well as all mixtures thereof, areincluded within the scope of the invention.

Where stereochemical configuration at a given asymmetric center isdefined by structure, unless stated otherwise, the depictedconfiguration indicates stereochemistry relative to other asymmetriccenters in the molecule. Where stereochemical configuration is definedby chemical name, the designations (rel), (R*), and (S*) indicaterelative stereochemistry, while the designations (+), (−), (R), (S), and(abs) indicate absolute stereochemistry.

In the compounds of formula (I), where relative stereochemistry isdefined, the diastereomeric purity of the compound preferably is atleast 80%, more preferably at least 90%, still more preferably at least95%, and most preferably at least 99%. As used herein, the term“diastereomeric purity” refers to the amount of a compound having thedepicted relative stereochemistry, expressed as a percentage of thetotal amount of all diastereomers present.

In some embodiments, stereochemical configurations depicted atasterisked positions indicate absolute as well as relativestereochemistry. Preferably, the enantiomeric purity of the compound isat least 80%, more preferably at least 90%, still more preferably atleast 95%, and most preferably at least 99%. As used herein, the term“enantiomeric purity” refers to the amount of a compound having thedepicted absolute stereochemistry, expressed as a percentage of thetotal amount of the depicted compound and its enantiomer.

Methods for determining diastereomeric and enantiomeric purity arewell-known in the art. Diastereomeric purity can be determined by anyanalytical method capable of quantitatively distinguishing between acompound and its diastereomers. Examples of suitable analytical methodsinclude, without limitation, nuclear magnetic resonance spectroscopy(NMR), gas chromatography (GC), and high performance liquidchromatography (HPLC). Similarly, enantiomeric purity can be determinedby any analytical method capable of quantitatively distinguishingbetween a compound and its enantiomer. Examples of suitable analyticalmethods include, without limitation, GC or HPLC, using a chiral columnpacking material. Enantiomers may also be distinguishable by NMR iffirst derivatized with an optically enriched derivatizing agent, e.g.,Mosher's acid.

In the compounds of formula (I), X is —CH₂—, —CHF—, —CF₂—, —NH—, or —O—.In some embodiments, X is —CH₂—, —NH—, or —O—. In certain embodiments, Xis —NH— or —O—. In certain particular embodiments, X is —O—.

In the compounds of formula (I), Y is —O—, —S—, or —C(R^(m))(R^(n))—,where R^(m) and R^(n) are as described above. In some embodiments, R^(m)is hydrogen, fluoro, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, orC₁₋₄ aliphatic. In some other embodiments, R^(m) and R^(n) together form═O. In other embodiments, R^(m) and R^(e), taken together with theintervening carbon atoms, form a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; or R^(m) and R^(e′), takentogether with the intervening carbon atoms, form a fused cyclopropanering, which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic. In certainembodiments, Y is —O— or —CH₂. In certain particular embodiments, Y is—CH₂.

In the compounds of formula (I), W is —CH₂—, —CHF—, —CF₂—, —CH(R¹)—,—CF(R¹)—, —NH—, —N(R¹)—, —O—, —S—, or —NHC(O)—, where R¹ is C₁₋₄aliphatic or C₁₋₄ fluoroaliphatic, or R¹ is a C₂₋₄ alkylene chain thatis attached to a ring position on Ring A to form a 5-, 6-, or 7-memberedfused ring, wherein the alkylene chain optionally is substituted withC₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, ═O, —CN, or —C(O)N(R⁴)₂. In someembodiments, W is —CH(R¹)— or —N(R¹), and R¹ is a C₂₋₃ alkylene chainthat is attached to a ring position on Ring A to form a 5- or 6-memberedfused ring, wherein the alkylene chain optionally is substituted withC₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, ═O, —CN, or —C(O)N(R⁴)₂. In someother embodiments, W is —CH₂—, —CHF—, —CF₂—, —NH—, —O—, —S—, or—NHC(O)—. In certain embodiments, W is —O—, —NH—, or —NHC(O)—. Incertain particular embodiments, W is —NH—.

In the compounds of formula (I), R^(a) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶,—NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or aC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with oneor two substituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); orR^(a) and R^(c) together form a bond. In some embodiments R^(a) isselected from the group consisting of hydrogen, fluoro, —CN, N₃, C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, —OR^(5x), —NH(R⁴), —N(H)CO₂R⁵,—N(H)C(O)R⁵, —C(O)NHR⁴, —C(O)R⁵, —OC(O)NHR⁴, —OC(O)R⁵, and —OC(O)OR⁵. Insome embodiments, R^(a) is selected from the group consisting ofhydrogen, —OH, —OCH₃, C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, and fluoro.In certain embodiments, R^(a) is selected from the group consisting ofhydrogen, —OH, —OCH₃, —CH₃, and fluoro. In certain particularembodiments, R^(a) is —OH.

In the compounds of formula (I), R^(c) is selected from the groupconsisting of hydrogen, fluoro, —CN, —N₃, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶,—NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or aC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with oneor two substituents independently selected from the group consisting of—OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); orR^(a) and R^(c) together form a bond. In some embodiments, R^(c) ishydrogen, fluoro, —CN, N₃, C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic,—OR^(5x), —NH(R⁴), —N(H)CO₂R⁵, —N(H)C(O)R⁵, —C(O)NHR⁴, —C(O)R⁵,—OC(O)NHR⁴, —OC(O)R⁵, and —OC(O)OR⁵. In certain embodiments, R^(c) ishydrogen, —OH, —OCH₃, or fluoro. In certain particular embodiments,R^(c) is hydrogen or —OH.

In the compounds of formula (I), R^(b) and R^(d) are each independentlyselected from the group consisting of hydrogen, fluoro, C₁₋₄ aliphatic,and C₁₋₄ fluoroaliphatic. In some embodiments, one of R^(b) and R^(d) isC₁₋₄ aliphatic and the other is hydrogen. In some embodiments, R^(b) andR^(d) are each hydrogen.

In one embodiment, R^(a) and R^(c) are each —OH, and R^(b) and R^(d) areeach hydrogen. In another embodiment, R^(a) is —OH, and each of R^(b),R^(c), and R^(d) is hydrogen. In another embodiment, R^(a) is —OH, R^(c)is fluoro or —OCH₃, and R^(b) and R^(d) are each hydrogen. In anotherembodiment, R^(a) is —OH, R^(b) is —CH₃, R^(c) is hydrogen or —OH, andR^(d) is hydrogen. In another embodiment, R^(a) and R^(c) together forma bond, and R^(b) and R^(d) are each hydrogen.

In the compounds of formula (I), each R^(f) independently is hydrogen,fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic; or two R^(f), takentogether with the carbon atom to which they are attached, form a 3- to6-membered cycloaliphatic ring; or one R^(f), taken together with R^(e)and the intervening carbon atoms, forms a 3- to 6-membered spirocyclicring; or two R^(f) together form ═O. In some embodiments, R^(f) is notfluoro if X is —O— or —NH—. In some embodiments, each R^(f)independently is hydrogen or C₁₋₄ aliphatic. In some such embodiments,each R^(f) independently is hydrogen or —CH₃. In certain embodiments,one R^(f) is hydrogen or —CH₃, and the other R^(f) is hydrogen. Incertain particular embodiments, each R^(f) is hydrogen.

In the compounds of formula (I), R^(e) is hydrogen or C₁₋₄ aliphatic; orR^(e), taken together with one R^(f) and the intervening carbon atoms,forms a 3- to 6-membered spirocyclic ring; or R^(e), taken together withR^(m) and the intervening carbon atoms, forms a fused cyclopropane ring,which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic. In someembodiments, R^(e) is hydrogen or C₁₋₄ aliphatic. In some suchembodiments, R^(e) is hydrogen or —CH₃. In certain embodiments, R^(e) ishydrogen.

In the compounds of formula (I), R^(e′) is hydrogen or C₁₋₄ aliphatic;or R^(e′), taken together with R^(m) and the intervening carbon atoms,forms a fused cyclopropane ring, which is optionally substituted withone or two substituents independently selected from fluoro or C₁₋₄aliphatic. In some embodiments, R^(e′) is hydrogen or C₁₋₄ aliphatic. Insome such embodiments, R^(e′) is hydrogen or —CH₃. In certainembodiments, R^(e′) is hydrogen.

In the compounds of formula (I), the variable m is 1, 2, or 3. In someembodiments, m is 1.

In the compounds of formula (I), Ring A is a 6-memberednitrogen-containing heteroaryl ring, optionally fused to a 5- or6-membered aryl, heteroaryl, cycloaliphatic or heterocyclic ring,wherein either or both rings are optionally substituted and one ringnitrogen atom is optionally oxidized. In some embodiments, Ring A is anoptionally substituted pyridine, pyrimidine, or 1,3,5-triazine ring. Inother embodiments, Ring A is a pyridine or pyrimidine ring that is fusedto a 5- or 6-membered aryl, heteroaryl, cycloaliphatic or heterocyclicring, wherein either or both rings are optionally substituted. In somesuch embodiments, Ring A is fused to an optionally substituted benzene,imidazole, pyrrole, or oxazole ring.

In some embodiments, the invention relates to a compound of formula (I)or a pharmaceutically acceptable salt thereof, characterized by one ormore of the following features:

-   -   (a) X is —O—;    -   (b) Y is —CH₂—;    -   (c) W is —NH—;    -   (d) R^(a) is —OH;    -   (e) R^(b) and R^(d) are each independently hydrogen or C₁₋₄        aliphatic;    -   (f) R^(c) is hydrogen, fluoro, or —OR⁵;    -   (g) R^(e) and R^(e′) are each hydrogen;    -   (h) each R^(f) is hydrogen; and    -   (i) m is 1.

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein Ring A and thevariables W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), andm have the values and preferred values described above for formula (I).

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (II), (II-A), or(II-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   D is —N═ or —C(R^(h))═;

E is —N═ or —C(R^(h))═;

R^(g) is hydrogen, halo, cyano, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R₆)═N—OR⁵, or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;

-   -   each R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂,        —SR⁶, or an optionally substituted C₁₋₄ aliphatic group; and    -   the variables W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e),        R^(e′), R^(f) and m have the values and preferred values        described above for formula (I).

In some embodiments, each R^(h) in formulae (II), (II-A), and (II-B)independently is hydrogen, halo, —CN, —OH, —O—(C₁₋₄ aliphatic), —NH₂,—NH—(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —SH, —S—(C₁₋₄ aliphatic), oran optionally substituted C₁₋₄ aliphatic group. In certain embodiments,each R^(h) independently is hydrogen, fluoro, —CH₃, —CF₃, or —OH. Incertain particular embodiments, R^(h) is hydrogen.

In some embodiments, Ring A is selected from the group consisting of:

In some embodiments, R^(g) is hydrogen, C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(1g), —R^(2g), -T¹-R^(1g), -T¹-R^(2g),—V¹-T¹-R^(1g), —V¹-T¹-R^(2g), —V¹—R¹, or -T¹-V¹—R^(1g), where thevariables R^(1g), R^(2g), V¹, and T¹ have the values described below.

T¹ is a C₁₋₆ alkylene chain substituted with 0-2 independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)—C(═NR⁴)—,—N(R⁴)CO₂—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —OC(O)—, —OC(O)N(R⁴)—, —C(O)—,—CO₂—, —C(O)N(R⁴)—, —C(═NR⁴)—N(R⁴)—, —C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or—C(R⁶)═N—O—, and wherein T¹ or a portion thereof optionally forms partof a 3-7 membered ring. In some embodiments, T¹ is a C₁₋₄ alkylene chainoptionally substituted with one or two groups independently selectedfrom fluoro, C₁₋₄ aliphatic, and C₁₋₄ fluoroaliphatic.

Each R^(3a) independently is selected from the group consisting of —F,—OH, —O(C₁₋₄ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₄ alkyl), —CO₂H, —CO₂(C₁₋₄alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₄ alkyl).

Each R^(3b) independently is a C₁₋₃ aliphatic optionally substitutedwith R^(3a) or R⁷, or two substituents R^(3b) on the same carbon atom,taken together with the carbon atom to which they are attached, form a3- to 6-membered cycloaliphatic ring.

Each R⁷ independently is an optionally substituted aryl or heteroarylring.

V¹ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—,—N(R⁴)C(═NR⁴)—, —N(R⁴)CO₂—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —OC(O)—,—OC(O)N(R⁴)—, —C(O)—, —CO₂—, —C(O)N(R⁴)—, —C(O)N(R⁴)—O—,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)—, —C(═NR⁴)—N(R⁴)—,—C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or —C(R⁶)═N—O—. In some embodiments, V¹ is—N(R⁴)C(O)—, —N(R⁴)C(O)N(R⁴)—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, or—N(R⁴)CO₂—. In certain such embodiments, V¹ is —N(R⁴)C(O)— or—N(R⁴)C(O)N(R⁴)—. In other embodiments, V¹ is —C(R⁵)═C(R⁵), —C≡C—, —O—,—S—, or —N(R⁴)—.

Each R^(1g) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring.

Each R^(2g) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.

The invention also relates to a subgenus of the compounds of formula(II), characterized by formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Q is -T¹- or —V¹-T¹-;    -   V¹ is —N(R⁸)—, —O—, or —S—;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   T¹ is a C₁₋₄ alkylene chain optionally substituted with one or        two groups independently selected from fluoro, C₁₋₄ aliphatic,        and C₁₋₄ fluoroaliphatic;    -   Ring C is a 3- to 8-membered heterocyclyl or cycloaliphatic        ring, or a 5- or 6-membered aryl or heteroaryl ring; and    -   the variables D, E, W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e),        R^(e′), R^(f), R^(h), and m have the values and preferred values        described above for formulae (I) and (II).

The invention also relates to a subgenus of the compounds of formula(III) characterized by formula (III-A), (III-B), (III-C), or (III-D):

or a pharmaceutically acceptable salt thereof, wherein all variables areas described for formula (III).

In some embodiments, Ring C is substituted with 0-2 R^(o) and 0-2R^(8o), where:

-   -   each R^(o) independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,        —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂,        —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,        —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,        —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂,        —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,        —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,        —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substituted        aliphatic, or an optionally substituted aryl, heterocyclyl, or        heteroaryl group; or two R^(o) on the same saturated ring carbon        atom, taken together with the carbon atom, form an optionally        substituted 3- to 8-membered spirocyclic cycloaliphatic or        heterocyclyl ring; or two adjacent R^(o), taken together with        the intervening ring atoms, form an optionally substituted fused        4- to 8-membered aromatic or non-aromatic ring having 0-3 ring        heteroatoms selected from the group consisting of O, N, and S;    -   each R^(8o) independently is selected from the group consisting        of C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, halo, —OR^(5x),        —N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic        optionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)),        —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); and    -   the variables R^(4x), R^(4y), and R^(5x) have the values        described above for formula (I).

In some such embodiments, Ring C is a C₃₋₆ cycloaliphatic, phenyl,pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrrolinyl,imidazolinyl, pyrazolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, morpholinyl, piperazinyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, or tetrahydropyrimidinyl ring, any of which issubstituted with 0-2 R^(o) and 0-2 R^(8o). In certain embodiments, RingC is a C₃₋₆ cycloaliphatic, phenyl, oxazolyl, or isoxazolyl ring, any ofwhich is substituted with 0-2 R^(8o) and optionally is fused to anoptionally substituted benzene, dioxolane, or dioxane ring.

The invention also relates to a subgenus of the compounds of formula(II), characterized by formula (IV), (IV-A), or (IV-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   V¹ is —N(R⁸)—, —O—, or —S—;    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   Ring D is an optionally substituted mono- or bicyclic ring        system; and the variables D, E, W, X, Y, R^(a), R^(b), R^(c),        R^(d), R^(e), R^(e′), R^(f), R^(h), and m have the values and        preferred values described above for formula (II).

In some embodiments, Ring D an optionally substituted furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl,pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,bicycloheptanyl or bicyclooctanyl. In some embodiments, Ring D is anoptionally substituted cyclopentyl or cyclohexyl. In some embodiments,Ring D is an optionally substituted indanyl, tetrahydronaphthyl, orchromanyl.

Ring D may be unsubstituted or may be substituted on either or both ofits component rings, and the substituents may be the same or different.In particular, each substitutable saturated ring carbon atom in Ring Dis unsubstituted or substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵,═N—NHC(O)R⁵, ═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(p). Each substitutableunsaturated ring carbon atom in Ring D is unsubstituted or substitutedwith —R^(p). Each substitutable ring nitrogen atom in Ring D isunsubstituted or substituted with —R^(9p). The variables R^(p) andR^(9p) have the values described below.

Each R^(p) independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵,—CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵,—C(R⁶)═N—OR⁵, or an optionally substituted aliphatic, or an optionallysubstituted aryl, heterocyclyl, or heteroaryl group; or two R^(p) on thesame saturated carbon atom, taken together with the carbon atom to whichthey are attached, form an optionally substituted 3- to 6-memberedspirocyclic cycloaliphatic ring.

Each R^(9p) independently is —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionally substituted with R³ or R⁷.

In some embodiments, each R^(p) independently is selected from the groupconsisting of halo, C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, —R^(1p),—R^(2p), -T²-R^(1p), and -T²-R^(2p); or two R^(p) on the same saturatedcarbon atom, taken together with the carbon atom to which they areattached, form an optionally substituted 3- to 6-membered spirocycliccycloaliphatic ring. The variables R^(1p), R^(2p), and T² have thevalues described below.

T² is a C₁₋₆ alkylene chain optionally substituted with R^(3a) orR^(3b).

Each R^(1p) independently is an optionally substituted aryl, heteroaryl,or heterocyclyl group.

Each R^(2p) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵,—SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.

In some embodiments, Ring D is selected from the group consisting of:

-   -   each R^(p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR^(5x),        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y));    -   each R^(8p) independently is selected from the group consisting        of fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or        —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄        fluoroaliphatic optionally substituted with —OR^(5x),        —N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or        two R^(8p) on the same carbon atom together form ═O or        ═C(R^(5x))₂; provided that R^(8p) is other than —OR^(5x) or        —N(R^(4x))(R^(4y)) when located at a position adjacent to a ring        oxygen atom;    -   s is 0, 1, 2, 3, or 4;    -   t is 0, 1, or 2; and    -   the variables R^(4x), R^(4y), R^(5x) have the values described        above for formula (I).

In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0, 1, 2,or 3. In certain embodiments, Ring D is selected from the groupconsisting of:

In certain particular embodiments, Ring D is selected from the groupconsisting of:

wherein stereochemical designations indicate absolute configurations.

The invention also relates to a subgenus of the compounds of formula(II), wherein:

-   -   R^(g) is —N(R⁸)(R⁹);    -   R⁸ is hydrogen or C₁₋₄ aliphatic;    -   R⁹ is hydrogen, C₁₋₄ aliphatic, -T³-R^(9a) or -T⁴-R^(9b);        -   T³ is a C₁₋₆ alkylene chain substituted with 0-2            independently selected R^(3a) or R^(3b);        -   T⁴ is a C₂₋₆ alkylene chain substituted with 0-2            independently selected R^(3a) or R^(3b);        -   R^(9a) is —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —S(O)R⁶, —SO₂R⁶,            —SO₂—N(R⁴)₂, —C(R⁵)═N—OR⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵,            —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, or —C(═NR⁴)—OR⁵; and        -   R^(9b) is halo, —NO₂, —CN, —OR⁵, —SR⁶, —N(R⁴)₂,            —N(R⁴)C(O)R⁵, —N(R⁴)C(O)N(R⁴)₂, —N(R⁴)CO₂R⁵, —O—CO₂—R⁵,            —OC(O)N(R⁴)₂, —OC(O)R⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)S(O)₂R⁶, or            —N(R⁴)SO₂—N(R⁴)₂.

In some such embodiments, R⁹ is hydrogen or a C₁₋₆ aliphatic or C₁₋₆fluoroaliphatic optionally substituted with one or two substituentsindependently selected from the group consisting of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)).

Another embodiment of the invention relates to a subgenus of thecompounds of formula (I) characterized by formula (V), (V-A), or (V-B):

or a pharmaceutically acceptable salt thereof, wherein:

Ring E is a 5- or 6-membered aryl, heteroaryl, cycloaliphatic orheterocyclic ring;

E is —N═ or —C(R^(h))═;

-   -   each R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂,        —SR⁶, or an optionally substituted C₁₋₄ aliphatic group;    -   each R^(k) independently is hydrogen, halo, —NO₂, —CN, —OR⁵,        —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,        —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶,        —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶,        —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,        —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵,        —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵,        —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl;

n is 0, 1, 2, or 3; and

the variables W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f),and m have the values and preferred values described above for formula(I).

In some embodiments, R^(k) is an optionally substituted C₁₋₆ aliphatic,or an optionally substituted 5- or 6-membered aryl, heteroaryl, orheteroaryl ring.

In some embodiments, the invention relates to a subgenus of thecompounds of formula (V) characterized by formula (VI), (VI-A), or(VI-B):

or a pharmaceutically acceptable salt thereof, wherein:

U is a covalent bond, C₁₋₃ alkylene, —O—, —S—, —S(O)—, or —S(O)₂—;

R^(8k) is halo, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;

Ring F is an optionally substituted mono-, bi-, or tricyclic ringsystem; and Ring E, and the variables E, W, X, Y, R^(a), R^(b), R^(c),R^(d), R^(e), R^(e′), R^(f), R^(h), and m have the values and preferredvalues described above for formula (V).

In some embodiments, Ring F is selected from the group consisting offuranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, carbazolyl, fluorenyl, dibenzofuranyltetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, dihydrobenzofuranyl, dihydrobenzothienyltetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, quinuclidinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, indanyl, phenanthridinyl, tetrahydronaphthyl,indolinyl, benzodioxanyl, benzodioxolyl, chromanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,bicycloheptanyl and bicyclooctanyl, any of which optionally issubstituted on any substitutable ring carbon atom and any substitutablering nitrogen atom.

In some embodiments, Ring F is selected from the group consisting ofthienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, phenyl, naphthyl, indolyl, isoindolyl, benzimidazolyl,benzthiazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl,naphthyridinyl, carbazolyl, fluorenyl, dibenzofuranyl,dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,benzodioxolyl, cyclopentyl, cyclohexyl, any of which optionally issubstituted on any substitutable ring carbon atom and any substitutablering nitrogen atom. In particular embodiments, Ring F is an optionallysubstituted phenyl, naphthyl, tetrahydronaphthyl, ordihydrobenzofuranyl.

In some embodiments, each substitutable ring nitrogen atom in Ring F isunsubstituted or is substituted with R^(9f), and the substitutable ringcarbon atoms are substituted with 0-4 R^(8f), wherein:

-   -   each R^(8f) independently is selected from the group consisting        of C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, halo, —OR^(5x),        —N(R^(4x))(R^(4y)), an optionally substituted 5- or 6-membered        aromatic ring, or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic        optionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)),        —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y));    -   R^(9f) independently is —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,        —SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionally substituted with R³        or R⁷; and    -   the variables R³, R^(4x), R^(4y), R^(5x), and R⁷ have the values        described above for formula (I).

The invention also relates to a subgenus of the compounds of formula (V)characterized by formula (VII), (VII-A), or (VII-B):

or a pharmaceutically acceptable salt thereof, wherein:

E is —N═ or —C(R^(h))═;

F is —N(R^(9k))—, —O—, or —S—;

G is ═N— or ═C(R^(k))—;

R^(9k) is hydrogen, —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, ora C₁₋₄ aliphatic optionally substituted with R³ or R⁷;

each R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂, —SR⁶,or an optionally substituted C₁₋₄ aliphatic group;

each R^(k) independently is hydrogen, halo, —NO₂, —CN, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; and

the variables W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f),R³, R⁴, R⁵, R⁶, R⁷, and m have the values and preferred values describedabove for formula (I).

In certain embodiments, the invention relates to a subgenus of thecompounds of formula (VII), characterized by formula (VII-C) or (VII-D):

or a pharmaceutically acceptable salt thereof, wherein:

dashed lines indicate single or double bonds;

each R^(2f) independently is hydrogen, halo, —OR^(5x),—N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); or both R^(2f), taken together with theintervening ring carbon atoms, form an optionally substituted fused 5-or 6-membered cycloaliphatic, aryl, heteroaryl, or heterocyclic ring.

The invention also relates to a subgenus of the compounds of formula (V)characterized by formula (VIII), (VIII-A), or (VIII-B):

or a pharmaceutically acceptable salt thereof, wherein:

the variables E, W, X, Y, R^(a), R^(b), R^(c), R^(d), R^(e), R^(e′),R^(f), R^(h), R^(k), and m have the values and preferred valuesdescribed above for formulae (VII), (VII-A), and (VII-B).

In some embodiments, R^(k) in formula (VII), (VII-A), (VII-B), (VIII),(VIII-A), or (VIII-B) has the formula —U-Ring F, wherein the variable Uand Ring F have the values and preferred values described above forformula (VI). In some such embodiments, the variable U is a covalentbond.

In a particular embodiment, the invention relates to a subgenus of thecompounds of formula (I), characterized by formula (IX-A) or (IX-B):

or a pharmaceutically acceptable salt thereof, wherein:

the variables D, E, R^(a), R^(b), R^(c), R^(d), R^(p), R^(8p), s, and thave the values and preferred values described above for formulae(I)-(IV).

In some embodiments, the stereochemical configurations depicted atasterisked positions in any preceding formula indicate relativestereochemistry. In other embodiments, stereochemical configurationsdepicted at asterisked positions indicate absolute stereochemistry. Incertain particular embodiments, the invention relates to compounds offormula (I-A), (II-A), (III-A), (IV-A) (V-A), (VI-A), (VII-A), (VIII-A),or (IX-A), wherein the stereochemical configurations depicted atasterisked positions indicate absolute stereochemistry.

Subgenus definitions for Ring A and variables W, X, Y, R^(a), R^(b),R^(c), R^(d), R^(e), R^(e′) and R^(f) described for formula (I) alsoapply to formulae (II)-(IX). Compounds embodying any combination of thepreferred values for the variables described herein are within the scopeof the present invention.

Representative examples of compounds of formula (I) are shown in Table1.

TABLE 1 E1 Activating Enzyme Inhibitors

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-45

I-46

I-47

I-48

I-49

I-53

I-54

I-55

I-56

I-58

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-71

I-73

I-74

I-76

I-77

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-92

I-93

I-94

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

The compounds in Table 1 above may also be identified by the followingchemical names:

Chemical Name

-   I-1    {(1R,2R,3S,4R)-4-[(6-{[(1S)-4-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-2    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methyl    sulfamate-   I-3    [(1R,2R,3S,4R)-2,3-dihydroxy-4-(9H-purin-6-ylamino)cyclopentyl]methyl    sulfamate-   I-4    [(1R,2R,3S,4R)-4-({2-[(cyclohexylmethyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-5    [(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-6    {(1R,2R,3S,4R)-4-[(6-{[(1S)-4,7-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-7    ((1R,2R,3S,4R)-4-{[2-(benzylamino)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methyl    sulfamate-   I-8    [(1R,2R,3S,4R)-4-({6-[(1R)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-9    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(8-phenyl-9H-purin-6-yl)amino]cyclopentyl}-methyl    sulfamate-   I-10    [(1R,2R,3S,4R)-2,3-dihydroxy-4-({2-[(3-methyl-2,3-dihydro-1H-inden-1-yl)-amino]pyrimidin-4-yl}amino)cyclopentyl]methyl    sulfamate-   I-11    [(1S,2R,3S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-12    [(1R,2R,3S,4R)-2,3-dihydroxy-4-({6-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidin-4-yl}amino)cyclopentyl]methyl    sulfamate-   I-13    {(1R,2R,3S,4R)-4-[(6-amino-2-methylpyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-14    [(1R,2R,3S,4R)-4-({6-[(cyclohexylmethyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-15    {(1R,2R,3S,4R)-4-[(2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-16    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(pyridin-3-ylcarbonyl)amino]cyclopentyl}-methyl    sulfamate-   I-17    {(1R,2R,3S,4R)-4-[(6-{[(1S)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-18    [(1R,2R,3S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-2-methylpyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-19    {(1R,2R,3S,4R)-4-[(6-{[(1S)-5-chloro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-20    [(1R,2R,3S,4R)-4-({2-[benzyl(methyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopenyl]methyl    sulfamate-   I-21    {(1R,2R,3S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-22    [(1R,2R,3S,4R)-4-({6-[benzyl(methyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-23    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(pyridin-2-ylcarbonyl)amino]cyclopentyl}-methyl    sulfamate-   I-24    {(1R,2R,3S,4R)-4-[(6-{[(1S)-4-chloro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-25    [(1R,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-26    [(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}-amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-27    ((1R,2R,3S,4R)-4-{[6-(benzylamino)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methyl    sulfamate-   I-28    [(1R,2R,3S,4R)-2,3-dihydroxy-4-(isonicotinoylamino)cyclopentyl]methyl    sulfamate-   I-29    [(1R,2R,3S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-30    ((1R,2R,3S,4R)-4-{[6-(benzylamino)-2-methylpyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methyl    sulfamate-   I-31    [(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methyl    sulfamate-   I-32    [(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-methylpyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methyl    sulfamate-   I-33    [(1S,2S,4S)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}methyl)-2-hydroxycyclopentyl]methyl    sulfamate-   I-34    ((1S,2S,4R)-4-{[8-(2-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-35    {(1S,2S,4R)-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-amino}pyridin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-36    {(1S,2S,4R)-2-hydroxy-4-[(7-methyl-8-phenyl-7H-purin-6-yl)-amino]cyclopentyl}methyl    sulfamate-   I-37    ((1S,2S,4R)-2-hydroxy-4-{[8-(2-phenoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methyl    sulfamate-   I-38    {(1S,2S,4R)-2-hydroxy-4-[(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]cyclopentyl}methyl    sulfamate-   I-39    {(1S,2S,4R)-4-[(8-dibenzo[b,d]furan-4-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-40    [(1S,2S,4R)-2-hydroxy-4-({6-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidin-4-yl}oxy)cyclopentyl]methyl    sulfamate-   I-41    ((1S,2S,4R)-4-{[8-(2,3-dihydro-1,4-benzodioxin-5-yl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-42    [(1S,2S,4R)-2-hydroxy-4-({6-[(1-naphthylmethyl)amino]pyrimidin-4-yl}-oxy)cyclopentyl]methyl    sulfamate-   I-43    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-45    [(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-6-methyl-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-46    ((1S,2S,4R)-2-hydroxy-4-{methyl[8-(1-naphthyl)-9H-purin-6-yl]amino}-cyclopentyl)methyl    sulfamate-   I-47    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)amino]cyclopentyl}methyl    sulfamate-   I-48    {(1S,2S,4R)-4-[(8-biphenyl-2-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methyl    sulfamate-   I-49    ((1S,2S,4R)-2-hydroxy-4-{[8-(1-naphthyl)-9H-purin-6-yl]amino}cyclopentyl)-methyl    sulfamate-   I-53    ((1S,2S,4R)-4-{[6-({(1S,2R)-2-[(dimethylamino)methyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-54    [(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-2-oxo-2,3-dihydropyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-55    {(1R,2R,3S,4R)-2,3-dihydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methyl    sulfamate-   I-56    ((1S,2S,4R)-4-{[6-chloro-2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-58    [(1R,3R,4R)-3-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-4-hydroxycyclopentyl]methyl    sulfamate-   I-60    ((1S,2S,4R)-4-{[8-(3-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-61    ((1S,2S,4R)-4-{[6-(3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-62    [(1S,2S,4R)-2-hydroxy-4-({8-[2-(trifluoromethoxy)phenyl]-9H-purin-6-yl}-amino)cyclopentyl]methyl    sulfamate-   I-63    {(1S,2S,4R)-2-hydroxy-4-[(8-phenyl-9H-purin-6-yl)oxy]cyclopentyl}methyl    sulfamate-   I-64    [(1S,2S,4R)-4-({8-[4-(dimethylamino)-1-naphthyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-65    {(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-66    ((1S,2S,4R)-4-{[6-({(1S,2S)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-67    ((1S,2S,4R)-4-{[8-(2,3-dimethoxyphenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-68    [(1S,2S,4R)-4-({8-[2-(benzyloxy)phenyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-69    {(1S,2S,4R)-2-hydroxy-4-[(8-phenyl-9H-purin-6-yl)amino]cyclopentyl}methyl    sulfamate-   I-71    {(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-5-fluoropyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-73    ((1S,2S,4R)-4-{[8-(7-chloroquinolin-4-yl)-7H-purin-6-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-74    ((1S,2S,4R)-2-hydroxy-4-{[6-(1-naphthyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amino}cyclopentyl)methyl    sulfamate-   I-76    [(1S,3R,4R)-3-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-4-hydroxycyclopentyl]methyl    sulfamate-   I-77    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-1-methoxy-2,3-dihydro-1H-inden-2-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-79    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-80    {(1S,2S,4R)-4-[(9-benzyl-9H-purin-6-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-81    ((1S,2S,4R)-2-hydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}cyclopentyl)-methyl    sulfamate-   I-82    N-({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl)sulfamide-   I-83    {(1S,2S,4R)-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-84    {(1S,2S,4R)-2-hydroxy-4-[(8-quinolin-8-yl-7H-purin-6-yl)amino]cyclopentyl}-methyl    sulfamate-   I-85    {(1R,2R,3S,4R)-4-[(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}pyrimidin-4-yl)-amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-86    ((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}-cyclopentyl)methyl    sulfamate-   I-87    ((1S,2S,4R)-2-hydroxy-4-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)methyl    sulfamate-   I-88    {(1S,2S,4R)-4-[(8-benzyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-89    [(1S,2S,4R)-4-({6-[(4-chlorobenzyl)oxy]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methyl    sulfamate-   I-90    {(1S,2S,4R)-2-hydroxy-4-[(2-phenyl[1,3]oxazolo[5,4-d]pyrimidin-7-yl)-amino]cyclopentyl}methyl    sulfamate-   I-92    {(1R,2R,3S,4R)-4-[(6-{[(1S,2S)-2-(benzyloxy)cyclopentyl]amino}pyrimidin-4-yl)-amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-93    ((1S,2S,4R)-4-{[8-(2,6-dimethoxyphenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-94    [(1S,2S,4R)-4-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyridin-4-yl}oxy)-2-hydroxycyclopentyl]methyl    sulfamate-   I-96    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-97 [(1S,2S,4R)-2-hydroxy-4-(pyrimidin-4-yloxy)cyclopentyl]methyl    sulfamate-   I-98    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-99    ((1S,2S,4R)-2-hydroxy-4-{[8-(3-methoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methyl    sulfamate-   I-100    ((1S,2S,4R)-4-{[8-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-9H-purin-6-yl]-amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-101    [(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfonyl]-9H-purin-6-yl}-oxy)cyclopentyl]methyl    sulfamate-   I-102    [(1S,2S,4R)-4-({8-[4-(benzyloxy)phenyl]-7H-purin-6-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-103    [(1S,2S,4R)-4-({8-[4-(dimethylamino)-1-naphthyl]-7H-purin-6-yl}oxy)-2-hydroxycyclopentyl]methyl    sulfamate-   I-105    {(1S,2S,4R)-4-[(8-biphenyl-3-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methyl    sulfamate-   I-106    {(1R,2R,3S,4R)-4-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-(methyl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-107    ((1S,2S,4R)-2-hydroxy-4-{[8-(2-methylphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methyl    sulfamate-   I-108    ((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(phenylethynyl)pyrimidin-4-yl]amino}-cyclopentyl)methyl    sulfamate-   I-109    ((1S,2S,4R)-2-hydroxy-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}-cyclopentyl)methyl    sulfamate-   I-110    (1S,2S,4R)-2-(hydroxymethyl)-4-{[8-(5,6,7,8-tetrahydronaphthalen-1-yl)-9H-purin-6-yl]amino}cyclopentanol-   I-111    ((1S,2S,4R)-4-{[8-(4-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-112    {(1S,2S,4R)-2-hydroxy-4-[(8-isoquinolin-4-yl-7H-purin-6-yl)oxy]cyclopentyl}-methyl    sulfamate-   I-113    [(1R,2R,3S,4R)-4-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoropyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methyl    sulfamate-   I-114    {(1S,2S,4R)-2-hydroxy-4-[(6-phenylpyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-115    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-117    ((1S,2S,4R)-4-{[8-(2,3-dihydro-1-benzofuran-7-yl)-7H-purin-6-yl]amino}-2-hydroxycyclopentyl)methyl    sulfamate-   I-118    ((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentyl)methyl    sulfamate-   I-119    ((1S,2S,4R)-2-hydroxy-4-{[6-(1-naphthylmethoxy)pyrimidin-4-yl]oxy}-cyclopentyl)methyl    sulfamate-   I-120    ((1S,2S,4R)-4-{[6-(1,3-dihydro-2H-isoindol-2-yl)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-121    ((1S,2S,4R)-2-hydroxy-4-{[8-(1,2,3,4-tetrahydronaphthalen-1-yl)-9H-purin-6-yl]-amino}cyclopentyl)methyl    sulfamate-   I-122    [(1S,2S,4R)-2-hydroxy-4-({8-[2-(trifluoromethyl)phenyl]-9H-purin-6-yl}-amino)cyclopentyl]methyl    sulfamate-   I-123    {(1S,2S,4R)-2-hydroxy-4-[methyl(9-methyl-8-phenyl-9H-purin-6-yl)-amino]cyclopentyl}methyl    sulfamate-   I-124    {(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-125    {(1S,2S,4R)-2-hydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methyl    sulfamate-   I-126    ((1S,2S,4R)-2-hydroxy-4-{[8-(5,6,7,8-tetrahydronaphthalen-1-yl)-9H-purin-6-yl]-amino}cyclopentyl)methyl    sulfamate-   I-127    ((1S,2S,4R)-4-{[6-(cyclopentylamino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-128    {(1S,2S,4R)-4-[(8-cyclohexyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methyl    sulfamate-   I-129    ((1S,2S,4R)-4-{[8-(1-benzyl-1H-pyrazol-4-yl)-7H-purin-6-yl]oxy}-2-hydroxycyclopentyl)methyl    sulfamate-   I-130    {(1S,2S,4R)-2-hydroxy-4-[(9-methyl-8-phenyl-9H-purin-6-yl)-amino]cyclopentyl}methyl    sulfamate-   I-131    {(1S,2S,4R)-4-[(8-tert-butyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-132    {(1S,2S,4R)-4-[(6-benzylpyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-133    ((1S,2S,4R)-2-hydroxy-4-{[8-(2-methoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methyl    sulfamate-   I-134    {(1S,2S,4R)-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-136    [(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfanyl]-7H-purin-6-yl}-oxy)cyclopentyl]methyl    sulfamate-   I-137    [(1S,2S,4R)-4-({8-[2-(dimethylamino)phenyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methyl    sulfamate-   I-138    (1S,2S,4R)-4-{[8-(2,3-dihydro-1,4-benzodioxin-5-yl)-9H-purin-6-yl]amino}-2-(hydroxymethyl)cyclopentanol-   I-139    ((1S,2S,4R)-2-hydroxy-4-{[8-(4-pyrrolidin-1-yl-1-naphthyl)-7H-purin-6-yl]oxy}-cyclopentyl)methyl    sulfamate-   I-140    ((1S,2S,4R)-2-hydroxy-4-{[8-(1H-indol-3-yl)-7H-purin-6-yl]oxy}cyclopentyl)-methyl    sulfamate-   I-141    ((1S,2S,4R)-2-hydroxy-4-{[6-(2-naphthylmethoxy)pyrimidin-4-yl]oxy}-cyclopentyl)methyl    sulfamate-   I-142    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-143    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-144    {(1R,2R,3S,4R)-4-[(2-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}pyridin-4-yl)amino]-2,3-dihydroxycyclopentyl}methyl    sulfamate-   I-145    ((1R,2R,3S,4R)-4-{[2-(2,3-dihydro-1H-indol-1-ylcarbonyl)pyridin-4-yl]amino}-2,3-dihydroxycyclopentyl)methyl    sulfamate-   I-146    ((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl    sulfamate-   I-147    {(1S,2S,4R)-4-[(4-{[(1R)-2,2-difluoro-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methyl    sulfamate-   I-148    {(1S,2S,4R)-4-[(6-{[(1S,2R)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-149    {(1S,2S,4R)-4-[(6-{[(1R,2S)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl    sulfamate-   I-150    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-151    {(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl    sulfamate-   I-152    ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)methyl    sulfamate-   I-153    [(1S,2S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}-amino)-2-hydroxycyclopentyl]methyl    sulfamate

General Synthetic Methodology

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in Schemes 1-21 below, and in the Examples.

Scheme 1 above shows a general route for preparing compounds of formula(I-B), wherein W is —NH— and R^(c) is —OH. Those of ordinary skill inthe art will recognize that compounds of formula (I-B) wherein Ring A isother than pyrimidine can be prepared by the same general route,beginning with appropriate starting materials analogous to ii.

As shown in Scheme 1, conversion of i to the compounds of formula iii isaccomplished by coupling with the appropriately substituted pyrimidinesat elevated temperature in protic solvents, such as EtOH or BuOH, usingan appropriate base, such as DIPEA or Et₃N in the presence of microwaveirradiation (Method A). Selective protection of the vicinal diol of iiiis effected at this stage by treatment with 2,2-dimethoxypropane in thepresence of an organic acid, such as p-TsOH in a solvent, such as MeOHor acetone (Method B). Displacement of the aryl chloride of formula ivis achieved by coupling with the appropriately substituted nucleophile,such as an amine, alcohol or thiol at elevated temperature usingmicrowave irradiation in the absence of solvent (Method C). Furthertreatment with freshly prepared chlorosulfonamide vi affords thesulfamates vii (Method D). Cleavage of the acetal by treatment with astrong acid, such as TFA, in the presence of water according to Method Eyields compounds of formula viii.

Compounds of formula (I-A) can be prepared by the methods described inScheme 2. Methods for the synthesis of the intermediate alkene diol ixare known (Nucleosides, Nucleotides & Nucleic Acids, 2002, 21, 65-72).Upon treatment with m-CPBA, diol ix is converted to epoxy diol x.Subsequent protection of the diol using p-anisaldehyde dimethyl acetalin the presence of pyridinium p-toluenesulfonate provides epoxide xi.Opening of the epoxide using a mixture of phthalimide and phthalimidepotassium salt in DMSO at elevated temperature affords alcohol xii. Thisalcohol is then alkylated by treatment with chlorophenylthionocarbonateand DMAP in DCM to afford thiocarbonate xiii (Method F). Deoxygenationat this stage is achieved by treatment with tris(trimethylsilyl)silaneand air in toluene followed by BEt₃ in toluene to give xiv (Method G).Subsequent deprotection with hydrazine in EtOH at elevated temperaturegives amine xv (Method H).

Conversion of amine xv to compounds of formula xvi is accomplished bycoupling with the appropriately substituted pyrimidines at elevatedtemperature in protic solvents, such as EtOH or BuOH, using anappropriate base, such as Et₃N in a sealed tube (Method I). Again, thoseof ordinary skill in the art will recognize that compounds of formulaxxi and xxii wherein Ring A is other than pyrimidine can be prepared bythe same general route, using a starting material analogous to ii.

The treatment of compounds having the general formula xvi with an amine,such as benzylamine, in the absence of solvent at elevated temperaturesusing microwave irradiation results in deprotection of the diol, andthen repeating the process in the presence of a base, such as DIPEA orEt₃N at elevated temperatures in a protic solvent, such as EtOH or BuOHusing microwave irradiation affords substituted pyrimidines xviii(Methods J and K).

Methods for the synthesis of tert-butyl chlorosulfonylcarbamate xix areknown (Hirayama et al., Biorg. Med. Chem., 2002, 10, 1509-1523), andthis reagent is reacted selectively with the primary alcohol using ahindered base, such as 2,6-di-tert-butyl-4-methylpyridine, in a solvent,such as ACN, to afford Boc sulfamates of formula xx (Method L). Removalof the siloxy group with a protic acid such as TFA (Method M) yields thecompounds of formula xxi.

Alternatively, compound xii can be directly exposed to the conditionsdescribed in Methods H-M, to afford dihydroxycyclopentyl methylsulfamates of formula xxii.

Compounds of formula (I-B), wherein W is —NHC(O)— can be prepared by themethods shown above in Scheme 3. Methods for the synthesis of bicycliclactam xxiii are known (Daluge et al., Nucleosides, Nucleotides &Nucleic Acids, 2000, 19, 297-327). Dihydroxylation using osmiumtetroxide in the presence of an organic N-oxide, such asN-methylmorpholine oxide, in a solvent, such as acetone, gives diolxxiv. Global protection of both alcohols using benzyl chloride and abase, such as Et₃N, and a catalyst, such as DMAP, in a solvent, such asDCM, gives compound xxv. The resulting bicyclic lactam is reduced usingNaBH₄ to afford Boc-protected amine xxvi, which is then deprotected upontreatment with HCl in the absence of water. The resulting secondaryamine hydrochloride xxvii is treated with an acyl chloride of formulaxxviii in the presence of a base, such as Et₃N or DIPEA, in an aproticsolvent, such as DCM to afford amides of formula xxix according toMethod N. The primary alcohol of xxx is then sulfamoylated by treatmentwith chlorosulfonamide vi and a base, such as DBU, in a polar aproticsolvent, such as ACN (Method O). Global deprotection of both secondaryalcohols using ammonia in a polar solvent, such as MeOH, yields finalsulfamates of formula xxxi (Method P).

Compounds of formula (I-B), wherein W is —NH— and R^(c) and R^(d) arehydrogen can be prepared by the methods shown above in Scheme 4. Aminodiol xxxii (Ober, M.; Muller, H.; Pieck, C.; Gierlich, J.; Carell, T. J.Am. Chem. Soc. 2005, 127, 18143-18149) is treated withdichloropyrimidines of formula ii according to Method I to givechloropyrimidines of formula xxxiii. Further reaction with anappropriately substituted nucleophile according to Method C or Method Kgives compounds of formula xxxiv. These diols are subsequentlyselectively sulfamoylated and deprotected according to Methods L-M asoutlined in Scheme 2.

Compounds of formula (I-B), wherein Ring A is a triazine ring, can beprepared as shown in Scheme 5. Coupling of cyanuric chloride xxxv with aprimary or secondary amine in a solvent such as THF using a base such asDIPEA at reduced temperature affords dichloride xxxvi. Displacement ofone chloride with amine hydrochloride xxxvii, followed by selectiveprotection of the vicinal hydroxyl groups using 2,2-dimethoxypropane inthe presence of pyridinium p-toluene sulfonate affords alcohol xxxix.Removal of the remaining aryl chloride using hydrogen in the presence ofpalladium on carbon (Method Q), followed by sulfamoylation usingchlorosulfonamide vi gives sulfamate xli.

Compounds of formula (I-A), wherein W is —O— can be prepared as depictedabove in Scheme 6. Methods for the synthesis of diol xlii are known(MacKeith et al., Biorg. Med. Chem., 1994, 2, 387-394), and this reagentis bis-protected using TBS-Cl and Et₃N in the presence of DMAP atelevated temperatures. Subsequent hydroboration-oxidation usingcatecholborane and Wilkinson's catalyst followed by NaOH, hydrogenperoxide and finally sodium sulfite yields cyclopentanol xliv. Thissecondary alcohol is deprotonated with the use of sodium hydride, andthen reacted with dichloropyrimidines of formula ii at reducedtemperature to afford coupled chloropyrimidines of formula xlv.Displacement of the aryl chloride is achieved by coupling with theappropriately substituted nucleophile, such as an amine, alcohol orthiol at elevated temperature using microwave irradiation in a solvent,such as BuOH (Method R). Global deprotection of the silyl ethers using afluoride reagent, such as TBAF according to Method S gives diols offormula xlvii. Compounds of formula xlvii are then selectivelysulfamoylated and deprotected according to Methods L-M as outlined inScheme 2.

Compounds of formula (I-B), wherein W is —NH— and Y=—O— can be preparedas shown above in Scheme 7. Methods for the synthesis of methylcarbamate xlviii are known (Nicolaou et al., J. Am. Chem. Soc., 2004,126, 6234-6235). Deprotection using an acid, such as HCl in the absenceof water affords amino alcohol il. Compound il is then substituted withthe appropriate substituents according to Methods A, then C-E andcarried on to compounds of formula (I-B) according to Scheme 1.

A general route for the synthesis of compounds of formula (I-B), whereinW is —NH—, Y=—O— and R^(c) is —H is outlined above in Scheme 8.Compounds of formula l are known (Kita, et al., J. Org. Chem., 1988, 53,554-561). Displacement of the aryl chloride using an appropriatelysubstituted nucleophile according to Method C gives pyrimidines offormula li. Compound li is then selectively sulfamoylated anddeprotected to give the final compounds according to Scheme 2 (MethodsL-M).

The synthesis of compounds of formula (I-A), wherein W is —S— and R^(c)is —OH is described in Scheme 9. The coupling of compounds of formulaliv with a nucleophile, such as an amine takes place in a solvent, suchas DMF to afford substituted compounds of formula lv (Method T).Subsequent opening of epoxide xi using a base, such as potassiumcarbonate in a solvent, such as DMF affords alcohol lvi (Method U).Compound lvi is then optionally deoxygenated (Methods F-G) andsubstituted with the appropriate substituents according to Methods J,then L-M and carried on to compounds of formula (I-A) according toScheme 2.

Compounds of formula (I-A), wherein W is —CH₂— can be prepared as shownabove in Scheme 10. Methyl pyrimidines of formula lvii are coupled witha nucleophile, such as an amine according to Method I to give2-chloropyrimidines of formula lviii. Hydro-dechlorination according toMethod Q gives methylpyrimidines of formula lviii. Deprotonation of themethyl group of lviii is effected by treatment with a strong base, suchas phenyllithium, and this carbanion is used to open epoxide xi (MethodV). Resulting compounds of formula lix are then optionally deoxygenated(Methods F-G), deprotected and selectively sulfamoylated (Methods J,then L-M) carried on to compounds of formula (I-A) according to Scheme2.

Compounds of formula (I), wherein W is —CH₂— and Y=—O— can be preparedabove in Scheme 11. Compound lx is known (Renz, et al., Liebigs Annalender Chemie, 1986, 6, 957-966). Coupling with an appropriatelysubstituted nucleophile, such as an amine according to Method K givesthe substituted, fully deprotected triol lxi. Compounds of formula lxiare then carried on according to Scheme 2 (Methods L-M).

Compounds of formula (I-B) wherein X=—NH— can be prepared by the methodsoutlined in Scheme 12. Methods for the synthesis of tert-butyl(aminosulfonyl)-carbamate lxii are known (Masui, et al., Tet. Lett.,2004, 45, 1853-1856). Compounds of formula iv are coupled with thiscarbamate in the presence of an azodicarboxylate, such as diisobutylazodicarboxylate in the presence of triphenylphosphine in a solvent,such as EtOAc to give Boc-protected compounds of formula lxiii (MethodW). These compounds are then substituted with the appropriatesubstituents and globally deprotected to give compounds of formula (I-B)according to Methods T and E (Schemes 9 and 1).

Compounds of formula (I-B) wherein X=CH₂ can be prepared by the methodsoutlined in Scheme 13. Compounds of formula v are oxidized using anoxidizing agent, such as Dess-Martin periodinane in a solvent, such asDCM (Method X). Methods for the synthesis of lxv are known (Carretero,et al., Tetrahedron., 1987, 43, 5125-5134), and this compound isdeprotonated using n-BuLi in THF and added to aldehyde lxiv to affordalkenes of formula lxvi. Reduction of the double bond using NaBH₄ inEtOH, followed by heating of the resulting sulfonate ester with Et₃N inDCM using microwave irradiation yields sulfonic acid lxviii. Treatmentwith thionyl chloride at reduced temperature in DCM in the presence of acatalyst, such as DMF gives sulfonyl chlorides of formula lxix. Finally,treatment with ammonia in a solvent, such as 1,4-dioxane in the presenceof DIPEA in DCM at reduced temperatures yields sulfonamides of formulalxx.

Compounds of formula (I-B) wherein X=CF₂ can be prepared by the methodsoutlined in Scheme 14. Carboxylic acid lxxi is decarboxylated usingsodium sulfate in water to give sulfonyl fluoride lxxii, which is thenconverted to the corresponding sulfonamide using ammonia in 1,4-dioxane.Boc-protection of the nitrogen using Boc anhydride in the presence ofDMAP and Et₃N in DCM yields Boc sulfonamide lxxiv. Deprotonation of theCF₂H group using a strong base, such as LiHMDS at reduced temperature ina solvent, such as THF followed by treatment with triflates of formulalxxvi (generated by treatment of alcohol lxxv with trifluoroaceticanhydride and Et₃N in DCM) gives compounds of formula lxxvii (Method Y).These compounds are then substituted with the appropriate substituentsand globally deprotected to give compounds of formula (I-B) according toMethods T and E (Schemes 9 and 1).

Compounds of formula (I) wherein X=CHF can be prepared by the methodsoutlined in Scheme 15. Methanesulfonyl chloride is coupled withbis(2,4-dimethoxybenzyl)-amine in the presence of Et₃N and DMAP in DCMto give sulfonamide lxxviii. Further treatment with n-BuLi and HMPA inTHF at reduced temperature followed by N-fluorobenzenesulfonimide givesfluoromethylsulfonamide lxxix. This compound is then taken on tocompounds of formula (I) by the procedures described in Scheme 14.

Compounds of formula (VII-A) wherein W=NH can be prepared by the methodsoutlined in Scheme 16. The sodium salt of lxxx, which is prepared as inExample 128a-c below, is condensed with a nitro aromatic lxxxi.Subsequently reduction with Zinc in acetic acid provides lxxxii.Oxidative coupling of an appropriate aldehyde such as napthaldehyde inthe presence of Na₂S₂O₅ provides compounds of the general formulalxxxiii. Deprotection with acetic acid in water/THF (Tetrahedron Lett.1998, 29, 6331) followed by sulfamation with chlorosulfonamide andconcomitant deprotection of the secondary hydroxyl provides compounds ofthe general formula VII-A.

Compounds of formula (VII-A) wherein W=O and R^(k)=—SO₂R⁶ can beprepared by the methods outlined in Scheme 17. The sodium salt of xlivis condensed with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine, whichis subsequently iodinated with NIS in THF to provide compound lxxxiv.The sodium salt of an aryl thiolate, such as 3-methylbenzenethiol, iscondensed in DMF to provide the intermediate lxxxv which, afterdeprotection and sulfamation as previously described, provides compoundlxxxvi. Exposure to oxidative conditions such as Oxone in aqueousmethanol provides compounds of general formula VI.

Compounds of formula (VII) wherein W=O and R^(k)=aryl and heteroaryl canbe prepared by the methods outlined in Scheme 18. Pd-mediated couplingof intermediates of the form lxxxiv with boronic acids providescompounds of form lxxxvii. Deprotection followed by sulfamation with achlorosulfonamide or diphenylcarbamoylsulfamoyl chloride (prepared in amanner similar to U.S. Pat. Appl. Publ. (2005), US 2005282797 A1)followed by removal of the secondary siloxy group with a protic acid,such as HCl, provides compounds of the general formula VII.

(S)-N-(2,3-dihydro-1H-inden-1-yl)indolin-4-amine is synthesized asillustrated in Scheme 19. Reduction of2-(4,6-dichloropyrimidin-5-yl)acetaldehyde with sodium borohydrideprovides alcohol lxxxviii, which is subsequently condensed with anappropriate aminoindane such as (S)-2,3-dihydro-1H-inden-1-amine toprovide the substituted pyrimidine lxxxix. Displacement under Mitsunobutype conditions with phthalimide and DIAD, followed by removal of thephthaloyl group with hydrazine, provides the amine intermediate xc.Cyclization under basic conditions provides the final compound(S)-N-(2,3-dihydro-1H-inden-1-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine.

Compounds of formula (VI) wherein W=NH can be prepared by the methodsoutlined in Scheme 20. Amine lxxx is condensed with chlorosubstitutedheterocycles of type xci to provide a product represented as xcii.Deprotection of the primary siloxy group with aqueous acetic acidfollowed by sulfamation with chlorosulfonamide ordiphenylcarbamoylsulfamoyl chloride provides intermediates of formxciii. Removal of the primary hydroxyl group with a Fluoride source,such as TBAF, or protic acid, such as HCl provides the final compound offormula VI.

As shown in Scheme 21, conversion of xciv (Ruediger, E; Martel, A;Meanwell, N; Solomon, C; Turmel, B. Tetrahedron Lett. 2004, 45, 739-742)to the compounds of formula I-A wherein W=NH is accomplished bypalladium catalyzed hydrogenation followed by mesylate formation to givexcv. Hydrogenolysis of the primary benzyl group followed by displacementof the mesylate using sodium azide in DMF yields xcvi. Exposure of xcvito hydrogenation conditions yields the desired amino alcohol xcvii,which can subsequently be used in coupling reactions with achloro-substituted heterocycle such as ii. Displacement of the arylchloride of formula xcviii is achieved by coupling with theappropriately substituted nucleophile, such as an amine, alcohol orthiol at elevated temperature using microwave irradiation in the absenceof solvent (see Method C). Further treatment with freshly preparedchlorosulfonamide vi followed by cleavage of the TBS-protecting groupusing a suitable reagent, such as TBAF, HF pyridine, or HCl. affords thesulfamates I-A as represented by xcxix.

Uses of Compounds of the Invention

The compounds of this invention are useful inhibitors of E1 enzymeactivity. In particular, the compounds are designed to be inhibitors ofNAE, UAE, and/or SAE. Inhibitors are meant to include compounds whichreduce the promoting effects of E1 enzymes in ubl conjugation to targetproteins (e.g., reduction of ubiquitination, neddylation, sumoylation),reduce intracellular signaling mediated by ubl conjugation, and/orreduce proteolysis mediated by ubl conjugation (e.g., inhibition ofcullin-dependent ubiquitination and proteolysis (e.g., theubiquitin-proteasome pathway)). Thus, the compounds of this inventionmay be assayed for their ability to inhibit the E1 enzyme in vitro or invivo, or in cells or animal models according to methods provided infurther detail herein, or methods known in the art. The compounds may beassessed for their ability to bind or mediate E1 enzyme activitydirectly. Alternatively, the activity of compounds may be assessedthrough indirect cellular assays, or assays measuring downstream effectsof E1 activation to assess inhibition of downstream effects of E1inhibition (e.g., inhibition of cullin-dependent ubiquitination andproteolysis). For example, activity may be assessed by detection ofubl-conjugated substrates (e.g., ubl-conjugated E2s, neddylated cullins,ubiquitinated substrates, sumoylated substrates); detection ofdownstream protein substrate stabilization (e.g., stabilization of p27,stabilization of IκB); detection of inhibition of UPP activity;detection of downstream effects of protein E1 inhibition and substratestabilization (e.g., reporter assays, e.g., NFκB reporter assays, p27reporter assays). Assays for assessing activities are described below inthe Experimental section and/or are known in the art.

One embodiment of this invention relates to a composition comprising acompound of this invention or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. It will beappreciated that the compounds of this invention may be derivatized atfunctional groups to provide prodrug derivatives which are capable ofconversion back to the parent compounds in vivo. Examples of suchprodrugs include the physiologically acceptable and metabolically labileester derivatives, such as methoxymethyl esters, methylthiomethylesters, or pivaloyloxymethyl esters derived from a hydroxyl group of thecompound or a carbamoyl moiety derived from an amino group of thecompound. Additionally, any physiologically acceptable equivalents ofthe present compounds, similar to the metabolically labile esters orcarbamates, which are capable of producing the parent compoundsdescribed herein in vivo, are within the scope of this invention.

If pharmaceutically acceptable salts of the compounds of the inventionare utilized in these compositions, the salts preferably are derivedfrom inorganic or organic acids and bases. For reviews of suitablesalts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) andRemington: The Science and Practice of Pharmacy, 20th Ed., ed. A.Gennaro, Lippincott Williams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

In certain particular embodiments, the invention relates to a baseaddition salt of a compound of formula I formed by deprotonation of thesulfamate (X=O) moiety, the sulfamide (X=NH) moiety, or the sulfonamide(X=CH₂) moiety, as applicable. In some such embodiments, the inventionrelates to a sodium or potassium salt of a compound of formula I.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The pharmaceutical compositions of the invention preferably are in aform suitable for administration to a recipient subject, preferably amammal, more preferably a human. The term “pharmaceutically acceptablecarrier” is used herein to refer to a material that is compatible withthe recipient subject, and is suitable for delivering an active agent tothe target site without terminating the activity of the agent. Thetoxicity or adverse effects, if any, associated with the carrierpreferably are commensurate with a reasonable risk/benefit ratio for theintended use of the active agent.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, solubilizing agents,bioavailability modifiers and combinations of these.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates or carbonates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intraperitoneal, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intravenously, or subcutaneously.The formulations of the invention may be designed to be short-acting,fast-releasing, or long-acting. Still further, compounds can beadministered in a local rather than systemic means, such asadministration (e.g., by injection) at a tumor site.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as, but not limited to, an oil, water, analcohol, and combinations of these. Solubilizing agents such ascyclodextrins may be included. Pharmaceutically suitable surfactants,suspending agents, or emulsifying agents, may be added for oral orparenteral administration. Suspensions may include oils, such as but notlimited to, peanut oil, sesame oil, cottonseed oil, corn oil and oliveoil. Suspension preparation may also contain esters of fatty acids suchas ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. Whenaqueous suspensions are required for oral use, the active ingredient iscombined with emulsifying and suspending agents. If desired, certainsweetening, flavoring or coloring agents may also be added. For oraladministration in a capsule form, useful diluents include lactose anddried cornstarch. In the case of tablets for oral use, carriers that arecommonly used include lactose and corn starch. Lubricating agents, suchas magnesium stearate, are also typically added. Coatings may be usedfor a variety of purposes; e.g., to mask taste, to affect the site ofdissolution or absorption, or to prolong drug action. Coatings may beapplied to a tablet or to granulated particles for use in a capsule.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The pharmaceutical compositions of this invention are particularlyuseful in therapeutic applications relating to disorders as describedherein (e.g., proliferation disorders, e.g., cancers, inflammatory,neurodegenerative disorders). Preferably, the composition is formulatedfor administration to a patient having or at risk of developing orexperiencing a recurrence of the relevant disorder being treated. Theterm “patient”, as used herein, means an animal, preferably a mammal,more preferably a human. Preferred pharmaceutical compositions of theinvention are those formulated for oral, intravenous, or subcutaneousadministration. However, any of the above dosage forms containing atherapeutically effective amount of a compound of the invention are wellwithin the bounds of routine experimentation and therefore, well withinthe scope of the instant invention. In certain embodiments, thepharmaceutical composition of the invention may further comprise anothertherapeutic agent. Preferably, such other therapeutic agent is onenormally administered to patients with the disorder, disease orcondition being treated.

By “therapeutically effective amount” is meant an amount of compound orcomposition sufficient, upon single or multiple dose administration, tocause a detectable decrease in E1 enzyme activity and/or the severity ofthe disorder or disease state being treated. “Therapeutically effectiveamount” is also intended to include an amount sufficient to treat acell, prolong or prevent advancement of the disorder or disease statebeing treated (e.g., prevent additional tumor growth of a cancer,prevent additional inflammatory response), ameliorate, alleviate,relieve, or improve a subject's symptoms of the a disorder beyond thatexpected in the absence of such treatment. The amount of E1 enzymeinhibitor required will depend on the particular compound of thecomposition given, the type of disorder being treated, the route ofadministration, and the length of time required to treat the disorder.It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, and diet of the patient, time ofadministration, rate of excretion, drug combinations, the judgment ofthe treating physician, and the severity of the particular disease beingtreated. In certain aspects where the inhibitor is administered incombination with another agent, the amount of additional therapeuticagent present in a composition of this invention typically will be nomore than the amount that would normally be administered in acomposition comprising that therapeutic agent as the only active agent.Preferably, the amount of additional therapeutic agent will range fromabout 50% to about 100% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent.

One embodiment of the invention relates to a method of inhibiting ordecreasing E1 enzyme activity in a sample comprising contacting thesample with a compound of this invention, or composition comprising acompound of the invention. The sample, as used herein, includes, withoutlimitation, sample comprising purified or partially purified E1 enzyme,cultured cells or extracts of cell cultures; biopsied cells or fluidobtained from a mammal, or extracts thereof; and body fluid (e.g.,blood, serum, saliva, urine, feces, semen, tears) or extracts thereof.Inhibition of E1 enzyme activity in a sample may be carried out in vitroor in vivo, in cellulo, or in situ.

In another embodiment, the invention provides a method for treating apatient having a disorder, a symptom of a disorder, at risk ofdeveloping, or experiencing a recurrence of a disorder, comprisingadministering to the patient a compound or pharmaceutical compositionaccording to the invention. Treating can be to cure, heal, alleviate,relieve, alter, remedy, ameliorate, palliate, improve or affect thedisorder, the symptoms of the disorder or the predisposition toward thedisorder. While not wishing to be bound by theory, treating is believedto cause the inhibition of growth, ablation, or killing of a cell ortissue in vitro or in vivo, or otherwise reduce capacity of a cell ortissue (e.g., an aberrant cell, a diseased tissue) to mediate adisorder, e.g., a disorder as described herein (e.g., a proliferativedisorder, e.g., a cancer, inflammatory disorder). As used herein,“inhibiting the growth” or “inhibition of growth” of a cell or tissue(e.g., a proliferative cell, tumor tissue) refers to slowing,interrupting, arresting or stopping its growth and metastases and doesnot necessarily indicate a total elimination of growth.

Disease applications include those disorders in which inhibition of E1enzyme activity is detrimental to survival and/or expansion of diseasedcells or tissue (e.g., cells are sensitive to E1 inhibition; inhibitionof E1 activity disrupts disease mechanisms; reduction of E1 activitystabilizes protein which are inhibitors of disease mechanisms; reductionof E1 activity results in inhibition of proteins which are activators ofdisease mechanisms). Disease applications are also intended to includeany disorder, disease or condition which requires effective cullinand/or ubiquitination activity, which activity can be regulated bydiminishing E1 enzyme activity (e.g., NAE, UAE activity).

For example, methods of the invention are useful in treatment ofdisorders involving cellular proliferation, including, but not limitedto, disorders which require an effective cullin-dependent ubiquitinationand proteolysis pathway (e.g., the ubiquitin proteasome pathway) formaintenance and/or progression of the disease state. The methods of theinvention are useful in treatment of disorders mediated via proteins(e.g., NFκB activation, p27^(KiP) activation, p21^(WAF/CIP1) activation,p53 activation) which are regulated by E1 activity (e.g., NAE activity,UAE activity, SAE activity). Relevant disorders include proliferativedisorders, most notably cancers and inflammatory disorders (e.g.,rheumatoid arthritis, inflammatory bowel disease, asthma, chronicobstructive pulmonary disease (COPD), osteoarthritis, dermatosis (e.g.,atopic dermatitis, psoriasis), vascular proliferative disorders (e.g.,atherosclerosis, restenosis) autoimmune diseases (e.g., multiplesclerosis, tissue and organ rejection)); as well as inflammationassociated with infection (e.g., immune responses), neurodegenerativedisorders (e.g., Alzheimer's disease, Parkinson's disease, motor neuronedisease, neuropathic pain, triplet repeat disorders, astrocytoma, andneurodegeneration as result of alcoholic liver disease), ischemic injury(e.g., stroke), and cachexia (e.g., accelerated muscle protein breakdownthat accompanies various physiological and pathological states, (e.g.,nerve injury, fasting, fever, acidosis, HIV infection, canceraffliction, and certain endocrinopathies)).

The compounds and pharmaceutical compositions of the invention areparticularly useful for the treatment of cancer. As used herein, theterm “cancer” refers to a cellular disorder characterized byuncontrolled or disregulated cell proliferation, decreased cellulardifferentiation, inappropriate ability to invade surrounding tissue,and/or ability to establish new growth at ectopic sites. The term“cancer” includes, but is not limited to, solid tumors and bloodbornetumors. The term “cancer” encompasses diseases of skin, tissues, organs,bone, cartilage, blood, and vessels. The term “cancer” furtherencompasses primary and metastatic cancers.

In some embodiments, the cancer is a solid tumor. Non-limiting examplesof solid tumors that can be treated by the methods of the inventioninclude pancreatic cancer; bladder cancer; colorectal cancer; breastcancer, including metastatic breast cancer; prostate cancer, includingandrogen-dependent and androgen-independent prostate cancer; renalcancer, including, e.g., metastatic renal cell carcinoma; hepatocellularcancer; lung cancer, including, e.g., non-small cell lung cancer(NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of thelung; ovarian cancer, including, e.g., progressive epithelial or primaryperitoneal cancer; cervical cancer; gastric cancer; esophageal cancer;head and neck cancer, including, e.g., squamous cell carcinoma of thehead and neck; melanoma; neuroendocrine cancer, including metastaticneuroendocrine tumors; brain tumors, including, e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma; bone cancer; and soft tissue sarcoma.

In some other embodiments, the cancer is a hematologic malignancy.Non-limiting examples of hematologic malignancy include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the compound or composition of the invention isused to treat a patient having or at risk of developing or experiencinga recurrence in a cancer selected from the group consisting ofcolorectal cancer, ovarian cancer, lung cancer, breast cancer, gastriccancer, prostate cancer, and pancreatic cancer. In certain preferredembodiments, the cancer is selected from the group consisting of lungcancer, colorectal cancer, ovarian cancer and hematologic cancers.

Depending on the particular disorder or condition to be treated, in someembodiments, the E1 enzyme inhibitor of the invention is administered inconjunction with additional therapeutic agent or agents. In someembodiments, the additional therapeutic agent(s) is one that is normallyadministered to patients with the disorder or condition being treated.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disorder or condition are known as“appropriate for the disorder or condition being treated.”

The E1 inhibitor of the invention may be administered with the othertherapeutic agent in a single dosage form or as a separate dosage form.When administered as a separate dosage form, the other therapeutic agentmay be administered prior to, at the same time as, or followingadministration of the E1 inhibitor of the invention.

In some embodiments, the E1 enzyme inhibitor of the invention isadministered in conjunction with a therapeutic agent selected from thegroup consisting of cytotoxic agents, radiotherapy, and immunotherapyappropriate for treatment of proliferative disorders and cancer.Non-limiting examples of cytotoxic agents suitable for use incombination with the E1 enzyme inhibitors of the invention include:antimetabolites, including, e.g., capecitibine, gemcitabine,5-fluorouracil or 5-fluorouracil/leucovorin, fludarabine, cytarabine,mercaptopurine, thioguanine, pentostatin, and methotrexate;topoisomerase inhibitors, including, e.g., etoposide, teniposide,camptothecin, topotecan, irinotecan, doxorubicin, and daunorubicin;vinca alkaloids, including, e.g., vincristine and vinblastin; taxanes,including, e.g., paclitaxel and docetaxel; platinum agents, including,e.g., cisplatin, carboplatin, and oxaliplatin; antibiotics, including,e.g., actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin,idarubicin, doxorubicin and pegylated liposomal doxorubicin; alkylatingagents such as melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine, andcyclophosphamide; including, e.g., CC-5013 and CC-4047; protein tyrosinekinase inhibitors, including, e.g., imatinib mesylate and gefitinib;proteasome inhibitors, including, e.g., bortezomib; thalidomide andrelated analogs; antibodies, including, e.g., trastuzumab, rituximab,cetuximab, and bevacizumab; mitoxantrone; dexamethasone; prednisone; andtemozolomide.

Other examples of agents the inhibitors of the invention may be combinedwith include anti-inflammatory agents such as corticosteroids, TNFblockers, Il-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporine,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, methotrexate, andsulfasalazine; antibacterial and antiviral agents; and agents forAlzheimer's treatment such as donepezil, galantamine, memantine andrivastigmine.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examples are forthe purpose of illustration only and are not to be construed as limitingthe scope of the invention in any way.

EXAMPLES Abbreviations

-   AA ammonium acetate-   AcOH acetic acid-   ACN acetonitrile-   d days-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM dichloromethane-   DEAD diethylazodicarboxylate-   DIAD diisopropylazodicarboxylate-   DIPEA N,N-diisopropylethylamine-   DMAP N,N-dimethyl-4-aminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   Et₃N triethylamine-   FA formic acid-   H₂O water-   h hours-   HCl hydrochloric acid-   LC/MS liquid chromatography mass spectrum-   MeOH methanol-   MeOD d₄-methanol-   MgSO₄ magnesium sulfate-   m-CPBA meta-chloroperbenzoic acid-   min minutes-   MS mass spectrum-   MWI microwave irradiation-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   NIS N-iodosuccinimide-   TBAF tetra-n-butylammonium fluoride-   TEA triethylamine-   p-TsOH para-toluenesulfonic acid-   rt room temperature-   TFA trifluoroacetic acid-   THF tetrahydrofuran

Analytical LC-MS Methods

Spectra were obtained on a Hewlett-Packard HP1100 using the followingconditions:

FA Standard: Phenominex Luna 5 μm C18 50×4.6 mm column at 2.5 ml/mingradient of ACN containing 0 to 100 percent 0.1% Formic Acid in H₂O for3 minAA Standard: Phenominex Luna 5 m C18 50×4.6 mm column at 2.5 mil/mingradient of ACN containing 0 to 100 percent 10 mM Ammonium Acetate inH₂O for 3 min.FA Waters: Waters Symmetry C18 3.5 μm 4.6 mm×100 mm column at 1 ml/mingradient of ACN containing 0 to 95 percent 0.1% Formic Acid in H₂O for10 minAA Waters: Waters Symmetry C18 3.5 μm 4.6 mm×100 mm column at 1 ml/mingradient of ACN containing 0 to 75 percent 0.1% 10 mM Ammonium Acetatein methanol for 10 minFA Long: Waters Symmetry C18 3.5 μm 4.6 mm×100 mm column at 1 ml/mingradient of ACN containing 5 to 100 percent 0.1% Formic Acid in H₂O for12 minAA Long: Waters Symmetry C18 3.5 m 4.6 mm×100 mm column at 1 ml/mingradient of ACN containing 5 to 100 percent 10 mM Ammonium Acetate inH₂O for 12 min

Example 1[(1R,2R,3S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-29) Step a:(1R,2S,3R,5R)-3-[(6-Chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diol

A mixture of(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride (200 mg, 1.09 mmol), 4,6-dichloropyrimidine (240. mg, 1.61mmol) and Et₃N (0.380 mL, 2.73 mmol) in EtOH (3.00 mL) was heated to150° C. for 15 min using MWI. The crude mixture was purified via silicagel chromatography eluting with a gradient of 0 to 15% MeOH in DCM toafford the title compound (255 mg, 90%). LC/MS: R_(t)=1.13 min, ES⁺ 260.(AA standard).

Step b:{(3aR,4R,6R,6aS)-6-[(6-Chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

A solution of(1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol(255 mg, 0.982 mmol), p-toluenesulfonic acid monohydrate (187 mg, 0.982mmol) and 2,2-dimethoxypropane (0.670 mL, 0.545 mmol) in MeOH (5.00 mL)was stirred overnight. The reaction was quenched via addition ofsaturated aqueous NaHCO₃ solution (10 mL) and MeOH was removed in vacuo.The aqueous mixture was extracted with DCM (4×20 mL) and the combinedorganics were concentrated in vacuo. The crude mixture was purified viasilica gel chromatography eluting with a gradient of 0 to 10% MeOH inDCM to afford the title compound (135 mg, 45.8%). LC/MS: R_(t)=1.77 min,ES⁺ 300. (AA standard).

Step c:[(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

A mixture of{(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(200 mg, 0.667 mmol) and (S)-(+)-1-aminoindan (0.188 mL, 1.47 mmol) wereheated to 180° C. for 3 h in a sealed tube using MWI. The mixture wasdissolved in DCM and the resulting suspension was washed with H₂Ofollowed by saturated ammonium chloride solution. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 0 to10% MeOH in EtOAc to afford the title compound as an amorphous solid(218 mg, 82.4%). LC/MS: R_(t)=1.44 min, ES⁺ 397 (AA standard).

Step d:[(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methylsulfamate

A 2.00 M solution of chlorosulfonamide in ACN was prepared as follows:FA (2.30 mL, 61.0 mmol) was added dropwise, with stirring tochlorosulfonyl isocyanate (5.20 mL, 59.7 mmol) under an atmosphere ofnitrogen at 0° C. After the addition was complete and the mixture hadsolidified, ACN (22.5 mL) was added. The resulting solution was left tostand under a vented source of nitrogen overnight at rt.

To a solution of[(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methanol(100. mg, 0.252 mmol) and Et₃N (0.0527 mL, 0.378 mmol) in DCM (2.50 mL)was added dropwise a 2.00 M solution of chlorosulfonamide in ACN (0.190mL, 0.380 mmol) at 0° C. and the mixture was stirred for 2 h. Thereaction was diluted with DCM, quenched with H₂O and the organic layerwas separated, then concentrated in vacuo. The residue was purified viasilica gel chromatography eluting with a gradient of 0 to 10% MeOH inDCM to afford the title compound (65.0 mg, 54%). LC/MS: R_(t)=1.58 min,ES⁺ 476 (AA standard).

Step e:[(1R,2R,3S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-29)

A solution of[(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methylsulfamate (60.0 mg, 0.126 mmol) was treated with a 9:1 mixture oftrifluoroacetic acid in H₂O (5.00 mL, 58.4 mmol) and the mixture wasstirred for 10 min before being concentrated in vacuo. The crudematerial was purified via reverse phase C18 preparative HPLC elutingwith a gradient of 5 to 70% of 0.1% FA/95% ACN/5% H₂O in 0.1% FA/99%H2O/1% ACN over 16 min to afford the title compound (27.0 mg, 49%). ¹HNMR (400 MHz, DMSO-d6, δ): 8.13 (s, 1H), 7.98 (s, 1H), 7.44 (s, 2H),7.28-7.02 (m, 5H), 6.72 (bs, 1H), 5.53 (s, 1H), 5.41 (s, 1H), 4.63 (d,J=5.3 Hz, 1H), 4.09 (dd, J=5.1, 9.5 Hz, 1H), 3.97 (dd, J=7.0, 9.5 Hz,1H), 3.81 (bs, 1H), 3.71-3.60 (m, 2H), 3.01-2.87 (m, 1H), 2.87-2.70 (m,1H), 2.47-2.37 (m, 1H), 2.30-2.09 (m, 2H), 1.89-1.72 (m, 1H), 1.19-1.05(m, 1H) ppm. LC/MS: R_(t)=1.13 min, ES⁺ 436 (AA standard).

Example 2{(1R,2R,3S,4R)-4-[(6-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-21) Step a:(2R)-2-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol

To a solution of 3,3-dimethylindan-1-one (925 mg, 5.77 mmol) and(R)-(−)-2-phenylglycinol (893 mg, 6.51 mmol) in toluene (10.0 mL) wasadded p-toluenesulfonic acid monohydrate (62.5 mg, 0.328 mmol). Thereaction was heated to reflux under an atmosphere of nitrogen for 90min. At this point, the mixture was cooled and diluted with toluene(10.0 mL). The mixture was washed with saturated aqueous NaHCO₃ solutionand H₂O. The organic layer was concentrated in vacuo and the residue wasdissolved in THF (10.0 mL) and cooled to 0° C. AcOH (1.13 mL, 19.9 mmol)was added, followed by sodium borohydride (251 mg, 6.64 mmol) and thereaction was allowed to warm to 23° C. overnight. The mixture waspartitioned between DCM and saturated aqueous NaHCO₃ solution. Theorganic layer was concentrated and silica gel chromatography elutingwith a gradient of 5 to 35% EtOAc in DCM afforded the title compound(1.49 g, 74%). LC/MS: R_(t)=1.92 min, ES⁺ 282 (AA standard).

Step b: (1S)-3,3-Dimethylindan-1-amine

A solution of(2R)-2-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol(1.44 g, 5.13 mmol) in MeOH (40.0 mL) was added to a stirred solution oflead tetraacetate (3.75 g, 8.03 mmol) in MeOH (60.0 mL) at 0° C.dropwise over 20 min. After stirring for 45 min, the reaction wasquenched via addition of a 10% solution of Na₂CO₃ in H₂O (76.0 mL) andthe mixture was stirred for 10 min. DCM (200 mL) was then added and thelayers were separated. The aqueous layer was extracted with DCM (50.0mL). The combined organic layers were concentrated in vacuo and theresidue was dissolved in EtOH (190. mL) and treated with a 10.4 Maqueous solution of HCl (5.70 mL, 59.3 mmol). The resulting mixture wasthen heated to reflux for 16 h. The cooled reaction was concentrated invacuo and partitioned between H₂O (150. mL) and Et₂O (50.0 mL). Theaqueous layer was adjusted to pH 10 via addition of Na₂CO₃ and extractedwith Et₂O (3×50.0 mL). The combined organic layers were concentrated invacuo and silica gel chromatography eluting with a gradient of 0 to 10%MeOH in DCM to afford the title compound as a pale yellow oil (420. mg,51%). ¹H NMR (CD₃OD, 300 MHz) δ: 7.34-7.14 (m, 4H), 4.45-4.37 (m, 1H),2.38 (dd, J=7.1, 12.4 Hz, 1H), 1.73 (bs, 2H), 1.60 (dd, J=8.7, 12.4 Hz,1H), 1.39 (s, 3H), 1.19 (s, 3H) ppm.

Step c:{(1R,2R,3S,4R)-4-[(6-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-21)

The title compound was prepared following the procedure described inExample 1a-e using (1S)-3,3-dimethylindan-1-amine in step c. ¹H NMR(CD₃OD, 400 MHz) δ: 7.95 (s, 1H), 7.28-7.15 (m, 4H), 5.62 (s, 1H), 5.38(bs, 1H), 4.22-4.12 (m, 2H), 3.92 (bs, 1H), 3.88 (dd, J=5.5, 5.5 Hz,1H), 3.78 (dd, J=5.5, 5.5 Hz, 1H), 2.46-2.27 (m, 3H), 1.84-1.76 (m, 1H),1.39 (s, 3H), 1.35-1.27 (m, 2H), 1.25 (s, 3H) ppm. LC/MS: R_(t)=1.42min, ES⁺ 464 (AA standard).

Example 3{(1R,2R,3S,4R)-4-[(6-{[(1S)-4-Chloro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-24)

The title compound was prepared following the procedure described inExample 2a-c using 4-chloroindan-1-one in step a. ¹H NMR (CD₃OD, 400MHz) δ: 8.01 (s, 1H), 7.26-7.15 (m, 4H), 5.69 (s, 1H), 5.44 (bs, 1H),4.17 (dddd, J=5.2, 9.7, 9.7, 9.8 Hz, 2H), 3.95 (bs, 1H), 3.88 (t, J=5.4Hz, 1H), 3.79 (t, J=5.6 Hz, 1H), 3.12-3.04 (m, 1H), 2.88 (ddd, J=8.2,8.2, 16.4 Hz, 1H), 2.66-2.56 (m, 1H), 2.43-2.28 (m, 2H), 1.99-1.88 (m,1H), 1.38-1.28 (m, 1H) ppm. LC/MS: R_(t)=1.08 min, ES⁺ 470. (FAstandard).

Example 4{(1R,2R,3S,4R)-4-[(6-{[(1S)-5,6-Difluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-17)

The title compound was prepared following the procedure described inExample 2a-c using 5,6-difluoroindan-1-one in step a. ¹H NMR (CD₃OD, 400MHz) δ: 7.96 (s, 1H), 7.14-7.02 (m, 3H), 5.62-5.58 (m, 1H), 5.39 (s,1H), 5.28 (bs, 1H), 4.22-4.13 (m, 2H), 3.89 (dd, J=5.5, 5.5 Hz, 1H),3.78 (dd, J=5.4, 5.4 Hz, 1H), 3.00-2.91 (m, 1H), 2.88-2.77 (m, 1H),2.64-2.55 (m, 1H), 2.44-2.32 (m, 1H), 1.97-1.86 (m, 1H), 1.43-1.20 (m,2H) ppm. LC/MS: R_(t)=1.02 min, ES⁺ 472 (FA standard).

Example 5{(1R,2R,3S,4R)-4-[(6-{[(1S)-4,7-Difluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-6)

The title compound was prepared following the procedure described inExample 2a-c using 4,7-difluoroindan-1-one in step a. ¹H NMR (CD₃OD, 400MHz) δ: 7.95 (s, 1H), 7.02-6.86 (m, 2H), 5.62-5.50 (m, 2H), 4.23-4.12(m, 2H), 3.92 (bs, 1H), 3.88 (dd, J=5.5, 5.5 Hz, 1H), 3.78 (dd, J=5.5,5.5 Hz, 1H), 3.16-3.05 (m, 1H), 2.95-2.85 (m, 1H), 2.62-2.50 (m, 1H),2.45-2.28 (m, 2H), 2.11-2.00 (m, 1H), 1.37-1.25 (m, 1H) ppm. LC/MS:R_(t)=0.94 min, ES⁺ 472 (FA standard).

Example 6{(1R,2R,3S,4R)-4-[(6-{[(1S)-4-Fluoro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-1)

The title compound was prepared following the procedure described inExample 2a-c using 4-fluoroindan-1-one in step a. ¹H NMR (CD₃OD, 300MHz) δ: 8.06 (s, 1H), 7.29-7.17 (m, 1H), 7.15-7.06 (m, 1H), 7.03-6.91(m, 1H), 5.75 (s, 1H), 5.42 (bs, 1H), 4.27-4.11 (m, 1H), 4.08-3.89 (m,2H), 3.89-3.80 (m, 1H), 3.16-3.02 (m, 1H), 2.96-2.80 (m, 1H), 2.73-2.55(m, 1H), 2.47-2.27 (m, 2H), 2.06-1.89 (m, 1H), 1.47-1.23 (m, 1H) ppm.LC/MS: R_(t)=0.94 min, ES⁺ 454 (FA standard).

Example 7[(1R,2R,3S,4R)-4-({6-[(1R)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-8)

The title compound was prepared following the procedure described inExample 1a-e using (R)-(−)-1-aminoindan in step c. ¹H NMR (CD₃OD, 400MHz) δ: 7.96 (s, 1H), 7.27-7.12 (m, 4H), 5.66 (s, 1H), 5.30 (bs, 1H),4.23-4.13 (m, 2H), 3.95 (bs, 1H), 3.90 (dd, J=5.5, 5.5 Hz, 1H), 3.80(dd, I=5.6, 5.6 Hz, 1H), 3.05-2.94 (m, 1H), 2.92-2.81 (m, 1H), 2.63-2.50(m, 1H), 2.45-2.28 (m, 2H), 1.96-7.80 (m, 1H), 1.38-1.27 (m, 1H) ppm.LC/MS: R_(t)=1.07 min, ES⁺ 436 (FA standard).

Example 8((1R,2R,3S,4R)-4-{[6-(Benzylamino)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-27)

The title compound was prepared following the procedure described inExample 1a-c using benzylamine in step c. ¹H NMR (CD₃OD, 300 MHz) δ:7.92 (s, 1H), 7.35-7.16 (m, 5H), 5.49 (s, 1H), 4.42 (s, 2H), 4.21-4.07(m, 2H), 3.91 (bs, 1H), 3.87 (dd, J=5.2, 5.2 Hz, 1H), 3.74 (dd, J=5.6,5.6 Hz, 1H), 2.39-2.19 (m, 2H), 1.46-1.11 (m, 1H) ppm. LC/MS: R_(t)=1.14min, ES⁻ 408 (AA standard).

Example 9[(1R,2R,3S,4R)-4-({6-[Benzyl(methyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-22)

The title compound was prepared following the procedure described inExample 1a-e using N-methylbenzyl amine in step c. ¹H NMR (CD₃OD, 300MHz) δ: 7.99 (s, 1H), 7.34-7.14 (m, 5H), 5.62 (s, 1H), 4.75 (s, 2H),4.23-4.09 (m, 2H), 4.01-3.90 (m, 1H), 3.87 (dd, J=5.5, 5.5 Hz, 1H), 3.76(dd, J=5.5, 5.5 Hz, 1H), 2.99 (s, 3H), 2.42-2.25 (m, 2H), 1.35-1.20 (1H)ppm. LC/MS: R_(t)=1.27 min, ES⁻ 422 (AA standard).

Example 10{(1R,2R,3S,4R)-4-[(6-{[(1S)-5-Chloro-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-19)

The title compound was prepared following the procedure described inExample 2a-c using 5-chloroindan-1-one in step a. ¹H NMR (CD₃OD, 400MHz) δ: 7.94 (s, 1H), 7.34-7.18 (m, 2H), 7.18-7.12 (m, 1H), 5.62 (s,1H), 5.30 (bs, 1H), 3.88 (dd, J=5.5, 5.5 Hz, 1H), 3.77 (dd, J=5.5, 5.5Hz, 1H), 3.03-294 (m, 1H), 2.92-2.81 (m, 1H), 2.61-2.51 (m, 1H),2.42-2.26 (m, 2H), 1.97-1.84 (m, 1H), 1.35-1.22 (m, 1H) ppm. LC/MS:R_(t)=1.44 min, ES⁻ 470. (AA standard).

Example 11[(1R,2R,3S,4R)-2,3-Dihydroxy-4-({6-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidin-4-yl}amino)cyclopentyl]methylsulfamate (Compound I-12)

The title compound was prepared following the procedure described inExample 1a-e using (S)-(+)-1,2,3,4-tetrahydro-1-napthylamine in step c.¹H NMR (CD₃OD, 400 MHz) δ: 7.93 (s, 1H), 7.27-7.20 (m, 1H), 7.18-7.06(m, 3H), 5.59 (s, 1H), 4.99 (bs, 1H), 4.23-4.11 (m, 2H), 3.92 (bs, 1H),3.88 (dd, J=5.5, 5.5 Hz, 1H), 3.77 (dd, J=5.5, 5.5 Hz, 1H), 2.90-2.70(m, 2H), 2.43-2.26 (m, 2H), 2.08-1.76 (m, 5H), 1.35-1.22 (m, 1H) ppm.LC/MS: R_(t)=1.33 min, ES⁺ 450. (AA standard).

Example 12{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methylsulfamate (Compound I-2) Step a: tert-Butyl[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate

(1R,2S)-1-Aminoindan-2-ol (1.83 g, 12.3 mmol) was dissolved in DCM (70.0mL) and TEA (3.42 mL, 24.5 mmol) was added. Di-tert-butyldicarbonate(2.81 g, 12.9 mmol) was added and the reaction mixture was stirred for 5h. The solution was concentrated in vacuo and purified via silica gelchromatography eluting with a gradient of 0 to 100% EtOAc in hexanes toafford the title compound (3.12 g, 100%). LC/MS: R_(t)=1.55 min, ES⁺250. (AA standard).

Step b: tert-Butyl[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate

A mixture of tert-butyl[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-carbamate (680. mg, 2.73mmol), DMF (21.1), barium monoxide (5.02 g, 32.7 mmol), barium hydroxide(2.80 g, 16.4 mmol) and iodomethane (1.70 mL, 27.3 mmol) was stirredovernight. LC/MS showed no starting material. The reaction was quenchedvia addition of a saturated solution of NaHCO₃ and was extracted withDCM. The organic layer was washed with H₂O (3×), dried over sodiumsulfate and concentrated in vacuo. The residue was purified via silicagel chromatography eluting with a gradient of 0 to 50% EtOAc in hexanesto afford the title compound (178 mg, 25%). LC/MS: R_(t)=1.24 min, ES⁺264 (AA standard).

Step c: (1R,2S)-2-Methoxyindan-1-amine

To tert-butyl [(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]carbamate(253 mg, 0.961 mmol) was added a 4.00 M solution of HCl in 1,4-dioxane(5.00 mL) and the mixture was stirred for 10 min, after which a whitesolid crashed out. The suspension was concentrated in vacuo andco-evaporated with toluene to afford a white solid, which was dissolvedin H₂O. The solution was adjusted to pH 10. via addition of Na₂CO₃. Themixture was then extracted with Et₂O (3×30 mL) and the organic extractswere concentrated in vacuo to afford the title compound (150. mg, 99%).LC/MS: R_(t)=0.85 min, ES⁺ 164 (AA standard).

Step d:{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methylsulfamate (Compound I-2)

The title compound was prepared following the procedure described inExample 2a-c using (1R,2S)-2-methoxyindan-1-amine in step a. ¹H NMR(CD₃OD, 400 MHz) δ: 7.97 (s, 1H), 7.28-7.10 (m, 4H), 5.36 (bs, 1H),4.21-4.10 (m, 3H), 3.93 (bs, 1H), 3.86 (t, J=5.4 Hz, 1H), 3.77 (t, J=5.6Hz, 1H), 3.32 (s, 3H), 3.12-2.95 (m, 2H), 2.44-2.26 (m, 2H), 1.38-1.25(m, 1H) ppm. LC/MS: R_(t)=0.94 min, ES⁺ 466 (FA standard).

Example 13[(1R,2R,3S,4R)-4-({6-[(Cyclohexylmethyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-14)

The title compound was prepared following the procedure described inExample 1a-e using cyclohexanemethylamine in step c. ¹H NMR (CD₃OD, 400MHz) δ: 8.08 (s, 1H), 5.69 (s, 1H), 4.22-4.13 (m, 2H), 4.00 (bs, 1H),3.89 (dd, J=5.2, 5.2 Hz, 1H), 3.82 (dd, J=6.2, 6.5 Hz, 1H), 3.18-3.07(m, 2H), 2.42-2.29 (m, 2H), 1.83-1.53 (m, 7H), 1.44-1.14 (m, 5H),1.07-0.92 (m, 2H) ppm. LC/MS: R_(t)=1.31 min, ES⁻ 414 (AA standard).

Example 14[(1R,2R,3S,4R)-2,3-Dihydroxy-4-({2-[(3-methyl-2,3-dihydro-1H-inden-1-yl)-amino]pyrimidin-4-yl}amino)cyclopentyl]methylsulfamate (Compound I-10) Step a: 3-Methylindan-1-one oxime

To a solution of 3-methylindan-1-one (221 mg, 1.51 mmol) andhydroxylamine hydrochloride (295 mg, 4.25 mmol) in MeOH (4.00 mL) wasadded a solution of NaOH (200 mg, 5.00 mmol) in H₂O (2.00 mL) and themixture was stirred at 80° C. for 2 h. The cooled reaction wasconcentrated in vacuo to remove most of the MeOH, and the residue waspartitioned between DCM and H₂O. The organic layer was concentrated invacuo to afford the title compound as a waxy solid (232 mg, 95%). LC/MS:R_(t)=1.51 min, ES⁺ 162 (AA standard).

Step b: 3-Methylindan-1-amine

A mixture of methylindan-1-one oxime (223 mg, 1.38 mmol) and 10%palladium on carbon (14.7 mg, 50% water wet) in MeOH (5.00 mL) wasstirred under an atmosphere of hydrogen overnight. The mixture was thenfiltered through celite, washed through with MeOH and the combinedfiltrates were concentrated in vacuo to afford the title compound (195mg, 96%). ¹H NMR (CDCl₃, 300 MHz) δ: 7.39-7.14 (m, 4H), 4.26 (dd, J=7.2,9.4 Hz, 1H), 3.13-2.96 (m, 1H), 2.71 (ddd, J=6.9, 6.9, 12.5 Hz, 1H),1.75 (bs, 2H), 1.35 (d, J=6.8 Hz, 3H), 1.25 (ddd, J=9.9, 9.9, 11.7 Hz,1H) ppm.

Step c:[(1R,2R,3S,4R)-2,3-Dihydroxy-4-({2-[(3-methyl-2,3-dihydro-1H-inden-1-yl)-amino]pyrimidin-4-yl}amino)cyclopentyl]methylsulfamate (Compound I-10)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a and3-methylindan-1-amine in step c. ¹H NMR (CD₃OD, 300 MHz) δ: 7.65-7.36(m, 1H), 7.34-7.04 (m, 5H), 6.23-5.99 (m, 1H), 5.62 (bs, 1H), 4.53-4.36(m, 1H), 4.22-4.09 (m, 2H), 3.94-3.81 (m, 2H), 3.25-3.08 (m, 1H),2.94-2.76 (m, 1H), 1.66-1.44 (m, 1H), 1.44-1.20 (m, 6H) ppm. LC/MS:R_(t)=1.19 min, ES⁺ 450. (AA standard).

Example 15{(1R,2R,3S,4R)-4-[(2-{[(1S)-3,3-Dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-15)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a and(1S)-3,3-dimethylindan-1-amine in step c. ¹H NMR (CD₃OD, 400 MHz) δ:8.47 (s, 1H), 7.59 (s, 1H), 7.32-7.17 (m, 4H), 6.06 (bs, 1H), 5.64 (bs,1H), 4.36 (bs, 1H), 4.21-4.09 (m, 2H), 3.91-3.81 (m, 2H), 2.47 (dd,J=7.3, 12.4 Hz, 1H), 2.41-2.23 (m, 2H), 1.91 (bs, 1H), 1.41 (s, 3H),1.26 (s, 3H), 0.99-0.88 (m, 1H) ppm. LC/MS: R_(t)=1.24 min, ES⁺ 464 (AAstandard).

Example 16[(1R,2R,3S,4R)-4-({2-[(Cyclohexylmethyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-4)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a andcyclohexanemethylamine in step c. ¹H NMR (CD₃OD, 400 MHz) δ: 7.50 (d,J=7.3 Hz, 1H), 6.04 (d, J=7.1 Hz, 1H), 4.42 (dd, J=7.9, 13.8 Hz, 1H),4.22-1.43 (m, 2H), 3.93-9.85 (m, 2H), 3.68 (s, 1H), 2.48-2.28 (m, 2H),1.84-1.55 (m, 7H), 1.37-1.13 (m, 5H), 1.07-0.93 (m, 2H) ppm. LC/MS:R_(t)=1.11 min, ES⁺ 416 (AA standard).

Example 17[(1R,2R,3S,4R)-4-({2-[Benzyl(methyl)amino]pyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-20)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a and N-methylbenzylamine in step c. ¹H NMR (CD₃OD, 400 MHz) δ: 7.59 (d, J=6.8 Hz, 1H),7.38-7.25 (m, 5H), 6.14 (d, J=6.6 Hz, 1H), 5.03-4.95 (m, 1H), 4.37 (bs,1H), 4.14 (d, J=4.6 Hz, 2H), 3.89-3.85 (m, 2H), 3.68 (s, 2H), 3.15 (s,3H), 2.86 (s, 1H), 2.35-2.22 (m, 2H), 1.28 (bs, 1H) ppm. LC/MS:R_(t)=1.16 min, ES⁺ 424 (AA standard).

Example 18((1R,2R,3S,4R)-4-{[2-(Benzylamino)pyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-7)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a and benzylamine instep c. ¹H NMR (CD₃OD, 400 MHz) δ: 7.58 (d, J=5.4 Hz, 1H), 7.36-7.26 (m,4H), 7.24-7.18 (m, 1H), 5.90 (d, J=6.3 Hz, 1H), 4.63-4.47 (m, 2H), 4.26(bs, 1H), 4.18-4.07 (m, 2H), 3.86 (dd, J=5.3, 5.3 Hz, 1H), 3.80 (dd,J=5.9, 6.3 Hz, 1H), 2.34-2.19 (m, 2H), 1.31-1.14 (m, 1H) ppm. LC/MS:R_(t)=1.07 min, ES⁺ 410. (AA standard).

Example 19[(1R,2R,3S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-2-methylpyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate and{(1R,2R,3S,4R)-4-[(6-amino-2-methylpyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compounds I-18 and I-13)

The title compounds were prepared following the procedure described inExample 1a-e using 4,6-dichloro-2-methylpyrimidine in step a and(S)-(+)-1-aminoindan in step c. Analytical data for[(1R,2R,3S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-2-methylpyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-18): ¹H NMR (CD₃OD, 400 MHz) δ: 7.31-7.14 (m, 4H),5.54 (s, 1H), 5.29 (bs, 1H), 4.22-4.11 (m, 2H), 3.92 (bs, 1H), 3.90 (dd,J=5.2, 5.2 Hz, 1H), 3.78 (dd, J=5.7, 5.7 Hz, 1H), 3.06-2.96 (m, 1H),2.93-2.82 (m, 1H), 2.63-2.52 (m, 1H), 2.40-2.31 (m, 2H), 2.29 (s, 3H),1.98-1.85 (m, 2H), 1.43-1.24 (m, 2H) ppm. LC/MS: R_(t)=1.29 min, ES⁺450. (AA standard). Analytical data for {(1R,2R,3S,4R)-4-[(6-amino-2-methylpyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}-methylsulfamate (Compound I-13): ¹H NMR (CD₃OD, 400 MHz) δ: 7.45 (s, 1H), 5.49(s, 1H), 4.25-4.11 (m, 2H), 3.95 (bs, 1H), 3.92 (dd, J=5.3, 5.8 Hz, 1H),3.78 (dd, J=5.8, 5.8 Hz, 1H), 2.69 (s, 1H), 2.44-2.31 (m, 1H), 2.27 (s,3H), 1.45-1.24 (m, 1H) ppm. LC/MS: R_(t)=0.76 min, ES⁺ 334 (AAstandard).

Example 20((1R,2R,3S,4R)-4-{[6-(Benzylamino)-2-methylpyrimidin-4-yl]amino}-2,3-dihydroxycyclopentyl)methylsulfamate (Compound I-30)

The title compound was prepared following the procedure described inExample 1a-e using 2,4-dichloropyrimidine in step a and benzylamine instep c. ¹H NMR (CD₃OD, 300 MHz) δ: 7.41-7.31 (m, 4H), 7.31-7.22 (m, 1H),5.55 (s, 11H), 4.52 (s, 2H), 4.21-4.09 (m, 2H), 3.87 (dd, J=4.9, 4.9 Hz,1H), 3.79 (dd, J=5.9, 6.8 Hz, 1H), 2.42 (s, 3H), 2.37-2.21 (m, 2H),1.41-1.21 (m, 2H) ppm. LC/MS: R_(t)=1.16 min, ES⁺ 424 (AA standard).

Example 21[(1R,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-25) Step a:(1S,2R,4R)-4-[(6-Chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol

To a neat mixture of (1S,2R,4R)-4-amino-2-(hydroxymethyl)cyclopentanol(3.00 g, 22.9 mmol) and 4,6-dichloropyrimidine (3.70 g, 24.8 mmol) wasadded isopropyl alcohol (30.0 mL) and Et₃N (8.00 mL, 57.4 mmol) and theresulting mixture was heated to 90° C. for 1 h. The mixture was thencooled to 23° C., filtered and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 5 to7% MeOH in DCM, and the compound was recrystallized from EtOAc to affordthe title compound as a white solid (3.30 g, 59%). LC/MS: R_(t)=0.84min, ES⁺ 244 (AA standard).

Step b:(1S,2R,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol

A mixture of(1S,2R,4R)-4-[(6-chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol(500. mg, 2.05 mmol), 1-butanol (4.00 mL) and (S)-(+)-1-aminoindan(0.806 mL, 6.16 mmol) was heated to 200° C. for 90 min in a sealed tubeusing MWI. The mixture was concentrated in vacuo and purified via silicagel chromatography eluting with a gradient of 5 to 25% MeOH in DCM toafford the title compound as an amorphous solid (513 mg, 73%). LC/MS:R_(t)=1.20 min, ES⁺ 341 (AA standard).

Step c: tert-Butyl (chlorosulfonyl)carbamate

To a stirred solution of chlorosulfonyl isocyanate (3.20 mL, 36.0 mmol)in benzene (15.0 mL) in a water bath at 23° C. was added tert-butylalcohol (3.50 mL, 36.2 mmol) dropwise via syringe under an atmosphere ofnitrogen. After 2 h, the mixture was diluted with hexanes (30.0 mL) andthe resulting white precipitate was filtered and washed with hexanes(3×20 mL). The collected solid was dried in a vacuum desiccator underhouse vacuum for 10 min to afford the title compound as a white solid(5.08 g, 65%). The product was stored under nitrogen in a freezer. ¹HNMR (300 MHz, CDCl₃, δ): 8.44 (bs, 1H), 1.57 (s, 9H) ppm. LC/MS:R_(t)=0.939 min, ES⁺ 215 (AA standard). Reference: F. Hirayama et al.,Biorg. Med. Chem., 2002, 10, 1509-1523.

Step d: tert-Butyl({[(1R,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methoxy}sulfonyl)carbamate

A neat mixture of(1S,2R,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol(100. mg, 0.294 mmol) and 2,6-di-tert-butyl-4-methylpyridine (181 mg,0.881 mmol) was dissolved in ACN (5.00 mL) before tert-butyl(chlorosulfonyl)carbamate (95.0 mg, 0.441 mmol, as prepared in Example21c) was added. The reaction was stirred for 2 h before being quenchedvia addition of MeOH (2 mL). The resulting mixture was concentrated invacuo and purified via silica gel chromatography eluting with a gradientof 10 to 20% MeOH in DCM to afford the title compound as an amorphoussolid (50.0 mg, 33%). LC/MS: R_(t)=1.24 min, ES⁺ 520. (AA standard).

Step e:[(1R,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-25)

To a solution of tert-butyl({[(1R,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methoxy}sulfonyl)carbamate(50.0 mg, 0.0962 mmol) in DCM (2.00 mL) was added trifluoroacetic acid(0.500 mL, 6.49 mmol), and the mixture was stirred for 30 min. Themixture was concentrated in vacuo and the residue was purified viasilica gel chromatography eluting with 10% MeOH in DCM, and the productwas dissolved in MeOH and treated with solid NaHCO₃. The suspension wasfiltered and the filtrate was purified via silica gel chromatographyeluting with 10% MeOH/DCM to afford the title compound as an amorphoussolid (12.0 mg, 30%). ¹H NMR (CD₃OD, 400 MHz) δ: 7.94 (s, 1H), 7.29-7.12(m, 4H), 5.53 (s, 1H), 5.32 (bs, 1H), 4.23-4.08 (m, 4H), 3.06-2.96 (m,1H), 2.93-2.82 (m, 1H), 2.61-2.50 (m, 1H), 2.45-2.34 (m, 1H), 2.26-2.15(m, 1H), 2.08-1.98 (m, 1H), 1.95-1.78 (m, 2H), 1.37-1.25 (m, 2H) ppm.LC/MS: R_(t)=1.29 min, ES⁺ 420. (AA standard).

Example 22{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[(8-phenyl-9H-purin-6-yl)amino]cyclopentyl}-methylsulfamate (Compound I-9)

The title compound was prepared following the procedure described inExample 1a-b, then 1d-e using 6-chloro-8-phenyl-9H-purine in step a. ¹HNMR (DMSO-d6, 400 MHz) δ: 13.4 (s, 1H), 8.28-8.10 (m, 4H), 7.76-7.64 (m,1H), 7.58-7.40 (m, 7H), 4.89-4.75 (m, 1H), 4.70-4.59 (m, 1H), 4.59-4.50(m, 1H), 4.15-4.07 (m, 2H), 4.06-3.99 (m, 1H), 3.91 (bs, 1H), 3.80-3.74(m, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.34-2.15 (m, 3H), 1.37-1.21 (m, 2H)ppm. LC/MS: R_(t)=1.14 min, ES⁺ 421 (AA standard).

Example 23[(1R,2R,3S,4R)-2,3-Dihydroxy-4-(9H-purin-6-ylamino)cyclopentyl]methylsulfamate (Compound I-3) Step a:[(3aR,4R,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

The title compound was prepared following the procedure described inExample 1b using(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride. ¹H NMR (CDCl₃, 300 MHz) δ: 4.76 (d, J=5.5 Hz, 1H), 4.20(d, J=4.8 Hz, 1H), 3.70 (dd, J=3.9, 11.3 Hz, 1H), 3.56-3.47 (m, 2H),3.05 (bs, 2H), 2.53-2.35 (m, 2H), 1.41 (s, 3H), 1.33-1.21 (m, 5H) ppm.

Step b:[(3aR,4R,6R,6aS)-2,2-Dimethyl-6-(9H-purin-6-ylamino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

The title compound was prepared following the procedure described inExample 1a using[(3aR,4R,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol.LC/MS: R_(t)=1.39 min, ES⁺ 306 (AA standard).

Step c:[(1R,2R,3S,4R)-2,3-Dihydroxy-4-(9H-purin-6-ylamino)cyclopentyl]methylsulfamate (Compound I-3)

A suspension of[(3aR,4R,6R,6aS)-2,2-dimethyl-6-(9H-purin-6-ylamino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(288 mg, 0.943 mmol) and Et₃N (0.400 mL, 2.87 mmol) in DCM (5.00 mL) wascooled to 0° C. A 2.00 M solution of chlorosulfonamide in ACN (0.94 mL,1.88 mmol, as prepared in Example 1d) was added dropwise, and DMF (1.50mL) was added to bring the mixture into solution. The solution wasallowed to warm to 23° C. and was stirred for 5 h before beingconcentrated in vacuo to dryness. The crude mixture was treated with a1.00 M solution of HCl in H₂O (5.00 mL, 5.00 mmol) and stirred for 10min. The mixture was concentrated to dryness and purified via reversephase C18 preparative HPLC eluting with a gradient of 0 to 40% of 0.1%FA/95% ACN/5% H₂O in 0.1% FA/99% H2O/1% ACN over 16 min to afford thetitle compound (95.0 mg, 29%). ¹H NMR (DMSO-d6, 400 MHz) δ: 12.9 (bs,1H), 8.25-8.01 (m, 2H), 7.68-7.29 (m, 3H), 5.12-4.30 (m, 3H), 4.10 (dd,J=5.8, 9.6 Hz, 1H), 4.01 (dd, J=7.0, 9.6 Hz, 1H), 3.85 (dd, J=5.6, 5.6,1H), 3.75 (dd, J=5.2, 5.2 Hz, 1H), 2.35-2.13 (m, 2H), 1.33-1.19 (m, 1H)ppm. LC/MS: R_(t)=1.02 min, ES⁺ 345 (AA standard).

Example 24[(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-5) Step a:(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol

(1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) wasdissolved in DCM (143 mL) and the solution was cooled to 0° C.3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixturewas stirred at 23° C. for 4 h. TLC indicated complete conversion. Silicagel (20 g) was added, the mixture was concentrated to dryness and waspurified via silica gel chromatography eluting with a gradient of 0 to100% EtOAc in DCM to afford the title compound (2.75 g, 76%). ¹H NMR(CDCl₃, 300 MHz) δ: 4.58 (d, J=8.1 Hz, 1H), 3.69 (s, 1H), 3.68 (s, 1H),3.60 (s, 1H), 3.52 (s, 1H), 2.47-2.40 (m, 1H), 2.14 (ddd, J=1.5, 10.2,15.3 Hz, 1H), 2.01 (dd, J=1.5, 15.3 Hz, 1H), 1.62 (bs, 2H) ppm. LC/MS:R_(t)=0.37 min, ES⁺ 131 (AA standard).

Step b:(1aS,1bR,5aS,6aS)-3-(4-Methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine

(1R,2R,3S,5S)-3-(Hydroxymethyl)-6-oxabicyclo[3.1.0]hexan-2-ol (3.65 g,21.0 mol) was dissolved in DCM (121 mL) and the solution was cooled to0° C. 1-(Dimethoxymethyl)-4-methoxybenzene (10.7 mL, 63.1 mmol) wasadded followed by pyridinium p-toluenesulfonate (530. mg, 2.11 mmol).The mixture was stirred at 23° C. overnight. TLC indicated completeconversion. The reaction mixture was concentrated in vacuo and theresidue was purified via silica gel chromatography eluting with agradient of 0 to 50% EtOAc in hexanes to afford the title compound (4.10g, 78%). ¹H NMR (CDCl₃, 400 MHz) δ: 7.44 (d, J=8.8 Hz, 2H), 6.89 (d,J=8.8 Hz, 2H), 5.93 (1H, s), 4.58 (d, J=8.4 Hz, 1H), 4.05 (s, 1H), 4.03(s, 1H), 3.80 (s, 3H), 3.71 (d, J=2.4 Hz, 1H), 3.51 (d, J=2.4 Hz, 1H),2.50-2.48 (m, 1H), 1.87 (ddd, J=1.6, 8.0, 14.8 Hz, 1H), 1.77 (d, J=14.8Hz, 1H) ppm. LC/MS: R_(t)=1.68 min, ES⁺ 249 (AA standard).

Step c:2-[(4aS,6R,7S,7aR)-7-Hydroxy-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione

To a neat mixture of(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)-hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(600. mg, 2.42 mmol), phthalimide (1.07 g, 7.25 mmol) and phthalimidepotassium salt (1.34 g, 7.25 mmol) was added DMSO (15.0 mL) and themixture was stirred at 120° C. for 18 h. The mixture was concentrated invacuo, treated with H₂O and extracted with EtOAc. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 0 to15% EtOAc in DCM to afford the title compound as a white solid (602 mg,63%). LC/MS: R_(t)=1.68 min, ES⁺ 396 (AA standard).

Step d:O-[(4aS,6R,7S,7aR)-6-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenylthiocarbonate

To a stirred solution of2-[(4aS,6R,7S,7aR)-7-hydroxy-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione(1.26 g, 3.19 mmol) in DCM (150. mL) was added DMAP (1.17 g, 9.54 mmol)and phenyl chlorothionoformate (0.661 mL, 4.78 mmol) under an atmosphereof argon. After 2 h, the mixture was concentrated in vacuo and theresidue was purified via silica gel chromatography eluting with agradient of 0 to 5% EtOAc in DCM to afford the title compound as a whiteamorphous solid (1.64 g, 97%). LC/MS: R_(t)=2.21 min, ES⁺ 532 (AAstandard).

Step e:2-[(4aS,6R,7aS)-2-(4-Methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione

To a solution ofO-[(4aS,6R,7S,7aR)-6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenylthiocarbonate (56.9 mg, 0.107 mmol) in toluene (4.00 mL) was addedtris(trimethylsilyl)silane (0.0700 mL, 0.227 mmol). Air (2.00 mL) wasbubbled through the solution and a 1.00 M solution of triethylborane inhexane (0.0320 mL, 0.0320 mmol) was added and the reaction was stirredfor 2 h. More tris(trimethylsilyl)silane (0.0700 mL, 0.227 mmol) and1.00 M triethylborane in hexane (0.0300 mL, 0.0300 mmol) were added, andthe mixture was stirred another 6 h. The mixture was then concentratedin vacuo and the residue was purified via silica gel chromatographyeluting with a gradient of 0 to 20% EtOAc in DCM to afford the titlecompound (16.9 mg, 42%). LC/MS: R_(t)=2.03 min, ES⁺ 380. (AA standard).

Step f:(4aS,6R,7aS)-2-(4-Methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-amine

A mixture of2-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione(390. mg, 1.03 mmol), EtOH (11.3 mL) and hydrazine (0.0362 mL, 1.13mmol) was stirred at 90° C. for 18 h. The resulting mixture was purifiedvia silica gel chromatography eluting with a gradient of 10 to 50% MeOHin DCM. LC/MS: R_(t)=1.08 min, ES⁺ 250. (AA standard).

Step g:6-Chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine

A sealed tube containing(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-amine(120. mg, 0.481 mmol), 4,6-dichloropyrimidine (143 mg, 0.963 mmol),DIPEA (0.0920 mL, 0.528 mmol) and EtOH (30.0 mL) was heated to 110° C.for 20 h. The cooled mixture was concentrated in vacuo and the residuewas purified via silica gel chromatography eluting with a gradient of 0to 5% MeOH in DCM (120. mg, 69%). LC/MS: R_(t)=1.74 min, ES⁺ 362 (AAstandard).

Step h:(1S,2S,4R)-4-[(6-Chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol

A neat mixture of6-chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine(120. mg, 0.332 mmol) and (S)-(+)-1-aminoindan (0.170 mL, 1.33 mmol) washeated to 180° C. for 6 h in a sealed tube using MWI. The reaction waspurified via silica gel chromatography eluting with a gradient of 0 to15% MeOH in DCM to afford the title compound (33.1 mg, 41%). LC/MS:R_(t)=0.90 min, ES⁺ 244 (AA standard).

Step i:(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol

A mixture of(1S,2S,4R)-4-[(6-chloropyrimidin-4-yl)amino]-2-(hydroxymethyl)cyclopentanol(33.1 mg, 0.136 mmol),6-chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine(81.6 mg, 0.226 mmol), (S)-(+)-1-aminoindan (0.222 mL, 1.73 mmol) and1-butanol (1.00 mL) was heated to 180° C. for 6 h in a sealed tube usingMWI. The reaction was purified via silica gel chromatography elutingwith a gradient of 0 to 15% MeOH in DCM to afford the title compound(77.8 mg, 63%). LC/MS: R_(t)=1.29 min, ES⁺ 341 (AA standard).

Step j:[(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-5)

The title compound was prepared following the procedure described inExample 21d-e using(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2-(hydroxymethyl)cyclopentanoland THF in step d. ¹H NMR (CD₃OD, 400 MHz) δ: 7.94 (s, 1H), 7.38-7.12(m, 5H), 5.51 (s, 1H), 5.32 (bs, 1H), 4.37-4.32 (m, 1H), 4.29 (dd,J=7.7, 9.7 Hz, 1H), 4.27-4.18 (m, 1H), 4.12 (dd, J=7.3, 9.7 Hz, 1H),3.05-2.96 (m, 1H), 2.93-2.82 (m, 1H), 2.60-2.51 (m, 1H), 2.51-2.42 (m,1H), 2.21 (ddd, J=1.8, 7.6, 13.9 Hz, 1H), 2.04-1.85 (m, 2H), 1.81 (ddd,J=4.9, 7.1, 13.8 Hz, 1H), 1.74-1.64 (m, 1H), 1.44 (s, 1H) ppm. LC/MS:R_(t)=1.38 min, ES⁺ 420. (AA standard).

Example 25[(1S,2R,3S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-11)

The title compound was prepared following the procedure described inExample 24 steps a-c, followed by steps f-g, and finally steps i-j. ¹HNMR (CD₃OD, 300 MHz) δ: 7.94 (s, 1H), 7.30-7.11 (m, 4H), 5.60 (s, 1H),5.30 (bs, 1H), 4.32 (dd, J=7.9, 9.4 Hz, 1H), 4.14-3.96 (m, 3H), 3.89(dd, J=3.8, 7.7 Hz, 1H), 3.08-2.95 (m, 1H), 2.87 (ddd, J=8.0, 8.0, 15.8Hz, 1H), 2.62-2.44 (m, 2H), 2.15-2.01 (m, 1H), 1.96-1.81 (m, 1H),1.70-1.57 (m, 1H) ppm. LC/MS: R_(t)=1.32 min, ES⁺ 436 (AA standard).

Example 26[(1R,2R,3S,4R)-4-({4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-26) Step a:4,6-Dichloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine

To a solution of cyanuric chloride (631 mg, 3.42 mmol) in THF (2.00 mL)at 0° C. was added (S)-(+)-1-aminoindan (0.385 mL, 3.00 mmol) and DIPEA(0.596 mL, 3.42 mmol) and the mixture was stirred at 0° C. for 2 h. Thereaction was then poured into H₂O, extracted with DCM and the organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified via silica gel chromatography eluting with agradient of 0 to 20% EtOAc in hexanes to afford the title compound as ayellow solid (738 mg, 87%). LC/MS: R_(t)=1.99 min, ES⁺ 281 (FAstandard).

Step b:(1R,2S,3R,5R)-3-({4-Chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol

A mixture of4,6-dichloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine(735 mg, 2.61 mmol),(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride (400. mg, 218 mmol), potassium carbonate (602 mg, 4.36mmol) and 1,4-dioxane (3.60 mL) in a sealed tube was heated to 150° C.for 20 mins using MWI. Silica gel chromatography eluting with a gradientof 2 to 7% MeOH in DCM afforded the title compound as a white solid(750. mg, 88%). LC/MS: R_(t)=1.42 min, ES⁺ 392 (FA standard).

Step c:[(3aR,4R,6R,6aS)-6-({4-Chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methanol

The title compound was prepared following the procedure described inExample 1b using(1R,2S,3R,5R)-3-({4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-5-(hydroxymethyl)cyclopentane-1,2-diol.LC/MS: R_(t)=1.81 min, ES⁺ 432 (FA standard).

Step d:[(3aR,4R,6R,6aS)-6-({4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}-amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

To a solution of[(3aR,4R,6R,6aS)-6-({4-Chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol(182 mg, 0.421 mmol) in EtOH (2.91 mL) was added 10% palladium on carbon(44.8 mg) and the mixture was placed under an atmosphere of hydrogen for2 d. Filtration of the mixture through a pad of celite, followed bysilica gel chromatography eluting with 5% MeOH in DCM afforded the titlecompound as a white solid (80.0 mg, 48%). LC/MS: R_(t)=1.24 min, ES⁺ 398(FA standard).

Step e:[(1R,2R,3S,4R)-4-({4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}-amino)-2,3-dihydroxycyclopentyl]methylsulfamate

The title compound was prepared following the procedure described inExample 1d using[(3aR,4R,6R,6aS)-6-({4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanoland pyridine. ¹H NMR (CD₃OD, 400 MHz) δ: 8.16-7.83 (m, 1H), 7.37-7.11(m, 3H), 5.68-5.45 (m, 1H), 4.39-4.00 (m, 3H), 3.91-3.77 (m, 1H),3.06-2.92 (m, 1H), 2.92-2.75 (m, 1H), 2.61-2.48 (m, 1H), 2.40-2.20 (m,2H), 2.02-1.79 (m, 2H), 1.37-1.17 (m, 1H) ppm. LC/MS: R_(t)=1.07 min,ES⁺ 437 (FA standard).

Example 27[(1R,2R,3S,4R)-2,3-Dihydroxy-4-(isonicotinoylamino)cyclopentyl]methylsulfamate (Compound I-28) Step a: tert-Butyl(1R,4S,5R,6S)-5,6-dihydroxy-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of tert-butyl(1R,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (500. mg, 2.39mmol) in acetone (20.0 mL) was added a 4% aqueous solution of osmiumtetroxide in H₂O (0.015 mL, 0.00239 mmol). To the resulting mixture wasadded a 10.2 M aqueous solution of N-methylmorpholine N-oxide (0.262 mL,2.67 mmol) dropwise over 1 h. At this point, a 0.240 M solution ofaqueous sodium bisulfite (1.00 mL, 0.240 mmol) was added, the mixturewas filtered through celite and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 20 to70% EtOAc in DCM to afford the title compound (420. mg, 72%). LC/MS:R_(t)=0.94 min, ES⁺ 244 (FA standard).

Step b: tert-Butyl(1R,4S,5R,6S)-5,6-bis(benzoyloxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate

A solution of tert-butyl(1R,4S,5R,6S)-5,6-dihydroxy-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate(2.00 g, 8.22 mmol), pyridine (5.00 mL, 61.8 mmol), Et₃N (2.29 mL, 16.4mmol) and DMAP (100. mg, 0.818 mmol) in DCM (5.00 mL) was cooled to 0°C. and benzoyl chloride (4.77 mL, 41.1 mmol) was added dropwise. Themixture was allowed to warm to 23° C. and stir for 2 h. The reaction wasthen diluted with DCM, washed with saturated aqueous NaHCO₃ (3×), copper(II) sulfate solution (3×) and water (3×). The organic layer was thendried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified via silica gel chromatography eluting with agradient of 5 to 40% EtOAc in hexanes to afford the title compound (2.92g, 79%). LC/MS: R_(t)=2.15 min, ES⁺ 452 (FA standard).

Step c:(1R,2S,3R,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diyldibenzoate

To a solution of tert-butyl(1R,4S,5R,6S)-5,6-bis(benzoyloxy)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate(2.09 g, 4.62 mmol) in MeOH (60.0 mL) was added sodium borohydride (700.mg, 18.5 mmol) at 0° C. and the reaction was allowed to warm to rt.After 1.5 h, the mixture was quenched with 1.00 N HCl solution (20.0mL), and concentrated in vacuo. The aqueous layer was extracted with DCM(3×50 mL) and the combined organic layers were washed with H₂O (100.mL), dried over MgSO₄ and concentrated in vacuo. The residue waspurified via silica gel chromatography eluting with a gradient of 20 to60% EtOAc in hexanes to afford the title compound (1.50 g, 80%). LC/MS:R_(t)=1.95 min, ES⁺ 456 (FA standard).

Step d: (1R,2S,3R,5R)-3-Amino-5-(hydroxymethyl)cyclopentane-1,2-diyldibenzoate hydrochloride

(1R,2S,3R,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diyldibenzoate (1.42 g, 3.11 mmol) was treated with a 4.00 M solution of HClin 1,4-dioxane (17.0 mL, 69.3 mmol) and the reaction was stirred for 35min. The reaction mixture was concentrated in vacuo and Et₂O was addedto precipitate the product, which was washed with Et₂O to afford thetitle compound as a white solid (1.05 g, 90%). LC/MS: R_(t)=1.06 min,ES⁺ 356 (FA standard).

Step e:(1S,2R,3R,5R)-3-(Hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyldibenzoate

A solution of(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoatehydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. wastreated with Et₃N (0.170 mL, 1.22 mmol) and stirred for 20 min.Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and themixture was stirred for 2 h. The reaction was treated with saturatedaqueous solution of ammonium chloride (50 mL) and extracted with DCM(2×50 mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedvia silica gel chromatography eluting with a gradient of 0 to 10% MeOHin DCM to afford the title compound (100. mg, 60%). LC/MS: R_(t)=1.49min, ES⁺ 461 (FA standard).

Step f:(1S,2R,3R,5R)-3-{[(Aminosulfonyl)oxy]methyl}-5-(isonicotinoylamino)cyclopentane-1,2-diyldibenzoate

To a solution of(1S,2R,3R,5R)-3-(hydroxymethyl)-5-(isonicotinoylamino)cyclopentane-1,2-diyldibenzoate (160. mg, 0.350 mmol) in ACN (10.0 mL) at 0° C. was added DBU(0.0600 mL, 0.401 mmol) and the mixture was stirred for 15 min. Afreshly prepared 1.40 M solution of chlorosulfonamide (0.500 mL, 0.700mmol, as prepared in Example 1d) was then added dropwise via syringe andthe mixture was stirred for 2.5 h at 0° C. before being allowed to warmto rt. The mixture was concentrated in vacuo and the residue waspurified via silica gel chromatography eluting with a gradient of 0 to10% MeOH in DCM to afford the title compound (50.0 mg, 27%). LC/MS:R_(t)=1.57 min, ES⁺ 540. (FA standard).

Step g:[(1R,2R,3S,4R)-2,3-dihydroxy-4-(isonicotinoylamino)cyclopentyl]methylsulfamate (Compound I-28)

A solution of(1S,2R,3R,5R)-3-{[(aminosulfonyl)oxy]methyl}-5-(isonicotinoylamino)cyclopentane-1,2-diyldibenzoate (61.1 mg, 0.113 mmol) in a 7.00 M solution of ammonia in MeOH(1.50 mL, 10.5 mmol) was stirred for 2 days. The reaction mixture wasthen concentrated in vacuo and purified via reverse phase C18preparative HPLC eluting with a gradient of 5 to 70% of 0.1% FA/95%ACN/5% H₂O in 0.1% FA/99% H2O/1% ACN over 16 min to afford the titlecompound (15.0 mg, 40%). ¹H NMR (CD₃OD, 300 MHz) δ: 8.67 (m, 2H), 7.78(m, 2H), 4.34-4.32 (m, 1H), 4.19-4.17 (m, 2H), 3.93-3.92 (m, 2H),2.38-2.31 (m, 1H), 1.76-1.72 (m, 1H), 1.43-1.38 (m, 1H) ppm. LC/MS:R_(t)=0.76 min, ES⁺ 332 (FA standard).

Example 28{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[(pyridin-2-ylcarbonyl)amino]cyclopentyl}-methylsulfamate (Compound I-23)

The title compound was prepared following the procedure described inExample 27a-e using pyridine-2-carbonyl chloride in step c. ¹H NMR(CD₃OD, 300 MHz) δ: 8.62 (s, 1H), 8.09-8.06 (m, 1H), 7.97-7.94 (m, 1H),7.55-7.51 (m, 1H), 4.34-4.32 (m, 1H), 4.19-4.18 (m, 2H), 3.95-3.93 (m,2H), 2.64 (s, 1H), 2.38-2.35 (m, 2H) ppm. LC/MS: R_(t)=1.23 min, ES⁺ 332(FA standard).

Example 29{(1R,2R,3S,4R)-2,3-Dihydroxy-4-[(pyridin-3-ylcarbonyl)amino]cyclopentyl}-methylsulfamate (Compound I-16)

The title compound was prepared following the procedure described inExample 27a-e using nicotinoyl chloride in step c. ¹H NMR (CD₃OD, 300MHz) δ: 8.97 (s, 1H), 8.67-8.66 (m, 1H), 8.26-8.23 (m, 1H), 7.55-7.50(m, 1H), 4.35-4.11 (m, 3H), 3.95-3.92 (m, 2H), 2.36-2.34 (m, 2H),1.43-1.38 (m, 1H) ppm. LC/MS: R_(t)=0.83 min, ES⁺ 332 (FA standard).

The following additional compounds were also prepared.

Example 30[(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate (Compound I-31)

The title compound was prepared in a manner similar to Example 34 using(S)-2-aminoindane. The title compound was prepared as a 4:1 mixture ofdesired compound and(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-TH-inden-1-ylamino]pyrimidin-4-yl}oxy)-2-(hydroxymethyl)cyclopentylsulfamate. Analytical data for[(1S,2S,4R)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate: ¹H NMR (CD₃OD, 300 MHz) δ: 8.13 (s, 1H), 7.28-7.12 (m, 4H),5.85 (s, 1H), 5.33-5.31 (m, 1H), 4.42-4.36 (m, 1H), 4.32 (dd, J=7.5, 9.7Hz, 1H), 4.15 (dd, J=7.2, 9.7 Hz, 1H), 3.06-2.97 (m, 1H), 2.93-2.82 (m,1H), 2.62-2.47 (m, 2H), 2.32-2.24 (m, 1H), 2.15 (s, 1H), 2.13-1.79 (m,4H) ppm. LC/MS: R_(t)=1.38 min, ES⁺ 422 (FA standard). Analytical datafor(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}oxy)-2-(hydroxymethyl)cyclopentylsulfamate: ¹H NMR (CD₃OD, 300 MHz) δ: 8.13 (s, 1H), 7.28-7.12 (m, 4H),5.85 (s, 1H), 5.33-5.31 (m, 1H), 5.14-5.07 (m, 1H), 4.59 (s, 1H), 3.78(dd, J=7.1, 11.0 Hz, 1H), 3.61 (dd, J=7.0, 11.1 Hz, 1H), 3.06-2.97 (m,1H), 2.73-2.61 (m, 1H), 2.61-2.47 (m, 2H), 2.32-2.24 (m, 1H), 2.17 (s,1H), 2.13-1.80 (m, 3H) ppm. LC/MS: R_(t)=1.38 min, ES⁺ 422 (FAstandard).

Example 31[(1S,2S,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-methylpyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate (Compound I-32)

The title compound was prepared in a manner similar to Example 34 using(S)-2-aminoindane and 4,6-dichloro-5-methylpyrimidine. ¹H NMR (CD₃OD,300 MHz) δ: 8.10 (s, 1H), 7.26-7.07 (m, 4H), 5.74 (t, J=7.9 Hz, 1H),5.59-5.49 (m, 1H), 4.45-4.37 (m, 1H), 4.34 (dd, J=7.5, 9.8 Hz, 1H), 4.16(dd, J=7.2, 9.7 Hz, 1H), 3.08-2.94 (m, 1H), 2.93-2.79 (m, 1H), 2.65-2.46(m, 2H), 2.37-2.23 (m, 1H), 2.18-2.13 (m, 3H), 2.13-1.90 (m, 2H), 1.89(s, 3H) ppm. LC/MS: R_(t)=1.55 min, ES⁺ 435 (FA standard).

Example 32[(1S,2S,4S)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-methyl)-2-hydroxycyclopentyl]methylsulfamate (Compound I-33)

The title compound was prepared according to Example 85. ¹H NMR (CD₃OD,400 MHz) δ: 8.34 (s, 1H), 7.27-7.15 (m, 4H), 6.41 (bs, 1H), 5.65-5.48(m, 1H), 4.30-4.25 (m, 2H), 4.09 (dd, J=4.1, 4.1 Hz, 1H), 3.07-3.00 (m,1H), 2.94-2.85 (m, 1H), 2.72-2.55 (m, 4H), 2.43-2.35 (m, 1H), 1.93-1.85(m, 2H), 1.75-1.67 (m, 1H), 1.58-1.51 (m, 2H) ppm. LC/MS: R_(t)=1.38min, ES⁺ 419 (AA standard).

Example 33((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)methylsulfamate (Compound I-152) Step a: 6-chloro-8-(1-naphthyl)-9H-purine

A mixture of 6-chloro-4,5-diaminopyrimidine (519 mg, 0.00359 mol) and1-naphthalenecarboxylic acid (618 mg, 0.00359 mol) in phosphorylchloride (2.0 mL, 0.021 mol) was heated at 110° C. under an atmosphereof nitrogen for 5.5 hours. The reaction was cooled and the residue waswashed several times with ether. The residue was dissolved in CH₂Cl₂ andaqueous NaHCO₃. The layers were separated and the aqueous was extractedwith EtOAc (1×) and CH₂Cl₂ (lx). The combined organics were washed withsaturated aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered, and collectedin vacuo to obtain 810 mg (80%) of an orange solid. LC/MS: R_(t)=1.68min, ES⁺ 261 (FA standard).

Step b: 6-chloro-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of 6-chloro-8-(1-naphthyl)-9H-purine (810 mg, 0.0029 mol)in THF (32.4 mL, 0.399 mol) was added pyridinium p-toluenesulfonate (70mg, 0.0003 mol) and dihydropyran (11.0 mL, 0.121 mol) and the mixturewas heated at 60° C. overnight. The reaction was cooled, quenched byaddition of saturated aqueous NaHCO₃ and the mixture was extracted withEtOAc (3×). The organic layers were combined, dried (Na₂SO₄), filteredand concentrated. The dark residue was purified by flash chromatography(10 to 40% EtOAc/hexanes) to obtain 534.5 (51%) mg of a light yellowsolid. LC/MS: R_(t)=2.03 min, ES⁺ 365 (FA standard).

Step c: (1S,3S)-3-(hydroxymethyl)cyclopentanol

To a solution of methyl (1S,3S)-3-hydroxycyclopentanecarboxylate (472.3mg, 0.003276 mol) in THF (13.2 mL) at 0° C. was added LiAlH₄ (145 mg,0.00382 mol) (WARNING: SIGNIFICANT GAS EVOLUTION). The mixture wasstirred for 1 hour at 0° C., then quenched at 0° C. by dropwise additionof water (145 μL, 0.00805 mol), 15% aqueous NaOH (145 μL) and water (435μL). The resulting gray suspension was stirred vigorously overnight. Theresulting off white suspension was filtered through celite and rinsedwith THF and MeOH. The combined organics were concentrated to obtain454.3 mg (>99%) an off-yellow solid. The material was carried on withoutfurther purification.

Step d: (1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol

To a solution of (1S,3S)-3-(hydroxymethyl)cyclopentanol (453.0 mg,0.003276 mol) and 1H-imidazole (669 mg, 0.00983 mol) in DMF (35.8 mL)under an atmosphere of nitrogen was added tert-butyldimethylsilylchloride (494 mg, 0.00328 mol). The mixture was stirred for 1.25 hours,then tert-butyldimethylsilyl chloride (49 mg, 0.00033 mol) was added.After an additional hour of stirring, the reaction was quenched withwater, extracted with ethyl acetate (3×), dried with anhydrous Na₂SO₄,filtered, and concentrated. The residue was filtered through a plug ofsilica with 30% EtOAc/hexanes to obtain 234.1 mg (31%) of the titlecompound.

Step e:6-{[(1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of(1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanol (111.0mg, 0.0004817 mol) (azeotroped with toluene) in DMF (3.6 mL) at 0° C.under an atmosphere of nitrogen was added sodium hydride (24.1 mg,0.000602 mol). The mixture was stirred for 15 min. To this cold solutionwas added a solution of6-chloro-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (163 mg,0.000401 mol) in DMF (1.8 mL). The flask was rinsed with DMF (1.0 mL))and this was added to the reaction as well. The resulting mixture wasstirred for 20 h. The reaction mixture was quenched with water and themixture was extracted with EtOAc (3×). The combined organic layers weredried over Na₂SO₄, filtered and collected in vacuo. The residue waspurified by flash chromatography (10 to 40% EtOAc/hexanes) to obtain156.9 mg (70%) of the title compound as a white solid.

Step f:((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)methanol

To a stirred solution of6-{[(1S,3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-8-(1-naphthyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(156.9 mg, 0.0002808 mol) in THF (3.8 mL) was added water (3.8 mL) andAcOH (7.6 mL), and the reaction mixture was stirred for 7 hours. Thereaction mixture was quenched by the slow addition of saturated NaHCO₃,and the resulting mixture was extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 5%MeOH/CH₂Cl₂) to obtain 85.7 mg (85%) of the title compound as a whitesolid. LC/MS: R_(t)=1.51 min, ES⁺ 361 (FA standard).

Step g: ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)methylsulfamate (Compound I-152)

To a solution of((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methanol(66.1 mg, 0.000183 mol) in DMA (8.12 mL) at 0° C. was addedchlorosulfonamide (106 mg, 0.000917 mol) in CH₃CN (2.0 mL). The reactionwas stirred at 0° C. for 10 mins, then 23° C. for 3 hours. The reactionwas quenched with water and extracted with EtOAc (3×). The combinedorganics were washed with water (2×), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography (0 to 6%MeOH/CH₂Cl₂) to obtain 56.3 mg (70%) of the title compound as a whitesolid. ¹H NMR (CD₃OD, 400 MHz) δ: 8.52-8.48 (m, 2H), 8.10-8.07 (m, 1H),8.01-7.98 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.57 (m, 3H), 5.89-5.85 (m,1H), 4.12-4.07 (m, 2H), 2.75-2.66 (m, 1H), 2.30-2.21 (m, 2H), 2.16-2.01(m, 2H), 1.93-1.85 (m, 1H), 1.62-1.53 (m, 1H) ppm. LC/MS: R_(t)=1.38min, ES⁺ 442 (FA standard).

Example 34{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-115) Step h:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine

To a suspension of sodium hydride (75.6 mg, 0.00189 mol) in THF (2 mL)at 0° C. under an atmosphere of nitrogen was added(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(0.60 g, 0.0017 mol) in 1.5 mL THF dropwise at 0° C. The mixture wasstirred at 0° C. for 10 min. To this was next added4,6-dichloro-pyrimidine (0.225 g, 0.00151 mol) in 2 mL THF at 0° C. Thesuspension was stirred at 0° C. for 2 hrs. The reaction was quenchedwith 9 mL saturated aqueous NH₄Cl and extracted with t-BuOMe (3×). Theorganic layers were combined and washed with brine, dried over anhydrousMgSO₄ and then concentrated to give 0.804 g of an oil. The residue waspurified by flash chromatography (0 to 10% EtOAc/hexanes) to give 0.63 g(80%) of the title compound.

Step b:6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-pyrimidin-4-amine

A mixture of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(260.0 mg, 0.0005494 mol), (1R,2S)-2-methoxyindan-1-amine (0.359 g,0.00220 mol) and triethylamine (115 μL, 0.000824 mol) in 1-butanol (0.97mL, 0.011 mol) was subjected to microwave irradiation (300 watts, 200°C.) for 30 minutes. The resulting dark brown mixture was filtered andconcentrated. The residue was purified by flash chromatography (0 to 15%EtOAc/hexanes) to give 0.26 g (79%) of the title compound. LC/MS:R_(t)=3.42 min, ES⁺ 600 (AA standard).

Step c:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol

A solution of6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({([tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine(0.32 g, 0.00053 mol) in THF (2.88 mL), water (2.88 mL), and acetic acid(8.64 mL) was stirred for 3 days. The reaction was concentrated andazeotroped 2× with toluene. The residue was purified by flashchromatography (30 to 80% EtOAc/hexanes) give 0.20 g (77%) of the titlecompound. LC/MS: R_(t)=1.59 min, ES⁺ 486 (FA standard).

Step d:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate

The title compound was prepared following the procedure described inExample 1 step d. LC/MS: R_(t)=2.16 min, ES⁺ 565 (FA standard).

Step e:{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-115)

To a solution of{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (0.239 g, 0.000423 mol) in pyridine (3.44 mL) and THF (3.44mL) was added pyridine hydrofluoride (0.953 mL, 0.0106 mol) dropwise.After stirring the reaction for 2 hours, an additional amount ofpyridine hydrofluoride (0.50 mL, 0.0055 mol) was added. After 2.75 hoursthe reaction was quenched by slow dropwise addition of saturated aqueousNaHCO₃ and extracted with EtOAc (4×). The combined organic phases weredried (Na₂SO₄), filtered and concentrated. The residue was purified byflash chromatography (0 to 10% MeOH/CH₂Cl₂) and then by preparativeplate chromatography (EtOAc) to obtain 100 mg (52%) of the titlecompound. ¹H NMR (CD₃OD, 400 MHz) δ: 8.15 (s, 1H), 7.24-7.15 (m, 4H),5.98 (s, 1H), 5.34 (bs, 1H), 4.41-4.38 (m, 1H), 4.32 (dd, 1H, J=7.5, 9.7Hz), 4.24-4.20 (m, 1H), 4.17 (dd, 1H, J=7.3, 9.8 Hz), 3.35 (s, 3H),3.13-3.00 (m, 3H), 2.57-2.48 (m, 1H), 2.31-2.25 (m, 1H) 2.12-1.93 (m,4H) ppm. LC/MS: R_(t)=1.33 min, ES⁺ 451 (FA standard).

Example 35{(1S,2S,4R)-2-hydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methylsulfamate (Compound I-125) Step a:(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol

A suspension of(1R,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopent-2-en-1-ol(7.54 g, 0.0225 mol) (Ruediger, E; Martel, A; Meanwell, N; Solomon, C;Turmel, B. Tetrahedron Lett. 2004, 45, 739-742), sodium carbonate (5.7g, 0.054 mol) and 10% Pd/C (2 g, 0.002 mol) in EtOAc (90 mL) was stirredunder an atmosphere of hydrogen for three hours. The reaction flask waspurged with nitrogen and the mixture was filtered through celite withEtOAc. The filtrate was concentrated to obtain 7.16 g (76%) of the titlecompound as a 4:1 mixture of diastereomers (desired:undesired).

Step b:(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentylmethanesulfonate

To a stirred solution of(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol(2.04 g, 0.00606 mol) in CH₂Cl₂ (96 mL) was added pyridine (2.4 mL,0.030 mol), DMAP (100 mg, 0.001 mol), and methanesulfonyl chloride (700μL, 0.0091 mol) under an atmosphere of nitrogen. The mixture was stirred23° C. for 45 minutes, then warmed to 40° C. for 3 hours. To thereaction was added DMAP (100 mg, 0.001 mol) and methanesulfonyl chloride(700 μL, 0.0091 mol). After stirring for 40 min, the reaction was cooledthen concentrated in vacuo. The residue was purified by flashchromatography (0 to 15% EtOAc/hexanes) to obtain 1.39 g (55%) of thetitle compound as one diastereomer (separated undesired diastereomerfrom step a).

Step c:({(1S,2S,4R)-4-azido-2-[(benzyloxy)methyl]cyclopentyl}oxy)(tert-butyl)-dimethylsilane

To a solution of(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanol(138.9 mg, 0.0004127 mol) and PPh₃ (118 mg, 0.000451 mol) in THF (2.7mL) at 0° C. was slowly added DEAD (71.1 μL, 0.000451 mol). The reactionwas stirred for 5 minutes, then diphenylphosphonic azide (97.4 μL,0.000452 mol) was added dropwise. The mixture was stirred for one hour.The reaction was partitioned with water and EtOAc. The layers wereseparated and the aqueous extracted with EtOAc (2×). The combinedorganics were washed with brine (1×), dried (Na₂SO₄), filtered, andcollected in vacuo. The residue was purified by flash chromatography (0to 10% EtOAc/hexanes) to obtain 93.5 mg (63%) of the title compound.

Step d:(1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentanamine

A suspension of({(1S,2S,4R)-4-azido-2-[(benzyloxy)methyl]cyclopentyl}-oxy)(tert-butyl)dimethylsilane(2.20 g, 0.00608 mol) and 10% Pd/C (0.16 g, 0.00015 mol) in EtOAc (23.9mL) was stirred under an atmosphere of hydrogen overnight. The reactionwas purged with nitrogen and the mixture filtered through celite withEtOAc. The filtrate was concentrated to obtain 2.01 g (98%) of the titlecompound.

Step e:4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine

To a solution of (1R,2S)-2-methoxyindan-1-amine (242.8 mg, 0.001488 mol)in THF (1 mL) was added cyanuric chloride (313 mg, 0.00170 mol) at 0°C., followed by DIPEA (300 μL, 0.002 mol) and the reaction was stirredat 0° C. for 1.5 hours. The reaction was poured into water and extractedwith CH₂Cl₂. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 15%EtOAc/hexanes) to obtain 229.1 mg (49%) of the title compound. LC/MS:R_(t)=2.03 min, ES⁺³¹¹ (FA standard).

Step f:N-((1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl)-6-chloro-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine

To a solution of(1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine(486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF(2.1 mL) was added4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine(410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. Thereaction was concentrated and the residue was purified by flashchromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of thetitle compound. LC/MS: R_(t)=2.96 min, ES⁺ 610 (FA standard).

Step g:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methanol

A suspension ofN-((1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentyl)-6-chloro-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine(250 mg, 0.00041 mol) and 10% Pd/C (44 mg, 0.000041 mol) in methanol(1.61 mL) was stirred under an atmosphere of hydrogen for 2 days. Thereaction was purged with nitrogen and filtered through celite withEtOAc. The filtrate was concentrated to obtain a yellow oil. The oil wastaken up in CH₂Cl₂ and saturated NaHCO₃. The layers were separated andthe aqueous was extracted with CH₂Cl₂ (1×). The combined organics weredried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (0 to 10% MeOH/CH₂Cl₂) to obtain 114 mg (57%) ofthe title compound. LC/MS: R_(t)=1.68 min, ES⁺ 486 (FA standard).

Step h:{(1S,2S,4R)-2-hydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methylsulfamate

The title compound was prepared following the procedure described inExample 34 steps d-e. ¹H NMR (compound exists as a ˜1:1 mixture ofrotamers by ¹H NMR) (CD₃OD, 400 MHz) δ: 8.03 and 7.92 [(d, J=4.6 Hz ands), 1H], 7.25-7.15 (m, 4H), 5.69 and 5.57 [(d, J=5.1 Hz and m), 1H],4.67-4.54 (m, 1H), 4.31-4.19 (m, 3H), 4.13-4.06 (m, 1H), 3.37 (s, 3H),4.13-2.98 (m, 2H), 2.53-2.43 (m, 1H), 2.19-2.14 (m, 1H), 2.06-1.98 (m,1H), 1.85-1.72 (m, 2H) ppm. LC/MS: R_(t)=1.07 min, ES⁺ 451 (FAstandard).

Example 36 [(1S,2S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-1,3,5-triazin-2-yl}-amino)-2-hydroxycyclopentyl]methyl sulfamate(Compound I-153)

The title compound was prepared in a fashion analogous to Example 35. ¹HNMR (compound exists as a ˜1:1 mixture of rotamers by ¹H NMR) (CD₃OD,400 MHz) δ: 8.03-8.00 and 7.91 [(m and s), 1H], 7.26-7.14 (m, 4H),5.66-5.50 (m, 1H), 4.65-4.57 (m, 1H), 4.33-4.25 (m, 2H), 4.12-4.08 (m,1H), 3.04-2.99 (m, 1H), 2.92-2.80 (m, 1H), 2.61-2.44 (m, 2H), 2.22-2.16(m, 1H), 2.04-1.71 (m, 4H) ppm. LC/MS: R_(t)=1.07 min, ES⁺ 421 (FAstandard).

Example 37[(1S,2S,4R)-2-hydroxy-4-({6-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]-pyrimidin-4-yl}oxy)cyclopentyl]methylsulfamate (Compound I-40)

The title compound was prepared in a fashion analogous to Example 34,steps a-c (using (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine in step b)and Example 65, step d to obtain the title compound. ¹H NMR (CD₃OD, 400MHz) δ: 8.12 (s, 1H), 7.22-7.08 (m, 4H), 5.77 (s, 1H), 5.30 (bs, 1H),4.40-4.28 (m, 2H), 4.17-4.13 (m, 1H), 2.89-2.71 (m, 2H), 2.54-2.47 (m,1H), 2.29-2.21 (m, 1H), 2.10-1.79 (m, 8H) ppm. LC/MS: R_(t)=6.66 min,ES⁺ 435 (FA long).

Example 38((1S,2S,4R)-4-{[6-(1,3-dihydro-2H-isoindol-2-yl)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-120)

The title compound was prepared in a fashion analogous to Example 34,steps a-c (using isoindoline in step b) and Example 65, step d to obtainthe title compound. ¹H NMR (D6-DMSO, 300 MHz) δ: 8.27 (s, 1H), 7.40-7.29(m, 4H), 5.81 (s, 1H), 5.47 (bs, 1H), 4.81 (d, 1H, J=4.4 Hz), 4.74 (bs,4H), 4.24-4.18 (m, 2H), 4.03-3.97 (m, 1H), 2.38 (bs, 1H), 2.22-2.14 (m,1H), 2.01-1.77 (m, 3H) ppm. LC/MS: R_(t)=6.40 min, ES⁺ 407 (FA long).

Example 39((1S,2S,4R)-4-{[6-(3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-61)

The title compound was prepared in a fashion analogous to Example 34,steps a-c (using tetrahydroisoquinoline in step b) and Example 65, stepd to obtain the title compound. ¹H NMR (CD3OD, 400 MHz) δ: 8.17 (s, 1H),7.17-7.14 (m, 4H), 5.93 (s, 1H), 4.63 (s, 2H), 4.39-4.30 (m, 2H),4.18-4.13 (m, 1H), 3.78-3.75 (m, 2H), 3.30 (s, 1H), 2.90-2.87 (m, 2H),2.54-2.47 (m, 1H), 2.30-2.24 (m, 1H), 2.09-1.91 (m, 3H) ppm. LC/MS:R_(t)=7.05 min, ES+ 421 (FA long).

Example 40 [(1S,2S,4R)-2-hydroxy-4-(pyrimidin-4-yloxy)cyclopentyl]methylsulfamate (Compound I-97) Step a:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}pyrimidine

A suspension of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(115.5 mg, 0.0002441 mol), sodium carbonate (62 mg, 0.00058 mol) and 10%Pd/C (26 mg, 0.000024 mol) in methanol (1.1 mL) was stirred under anatmosphere of hydrogen for 2 days. The reaction was purged with nitrogenand filtered through celite with EtOAc. The filtrate was concentratedand the residue was purified by flash chromatography (0 to 15%EtOAc/hexanes) to obtain 80 mg (70%) of the title compound.

Step b: [(1S,2S,4R)-2-hydroxy-4-(pyrimidin-4-yloxy)cyclopentyl]methylsulfamate

The title compound was prepared in a fashion analogous to Example 34,step b and Example 65, step d to obtain the title compound. ¹H NMR(CD₃OD, 400 MHz) δ: 8.70 (s, 1H), 8.40 (d, J=6.1 Hz, 1H), 6.83 (dd, J=1,6.1 Hz, 1H), 5.66-5.61 (m, 1H), 4.41-4.38 (m, 1H), 4.33 (dd, J=7.3, 9.8Hz), 4.16 (dd, J=7.2, 9.7 Hz), 2.58-2.48 (m, 1H), 2.36-2.30 (m, 1H),2.11-2.03 (m, 2H), 2.00-1.94 (m, 1H) ppm. LC/MS: R_(t)=4.08 min, ES+ 290(FA long).

Example 41[(1S,2S,4R)-4-({6-[(4-chlorobenzyl)oxy]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate (Compound I-89) Step a:4-{[(1R,3S,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(1,1,2,2-tetramethylpropoxy)cyclopentyl]oxy}-6-[(4-chlorobenzyl)oxy]pyrimidine

To a solution of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(0.205 g, 0.000433 mol) and 4-chlorobenzyl alcohol (0.130 g, 0.000910mol) in DMF (1 mL) under at atmosphere of nitrogen was added sodiumhydride (36.4 mg, 0.000910 mol) (60% in oil). The reaction was stirredfor 3.5 hours. The reaction was quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), filteredand concentrated. The residue by purified by flash chromatography (0 to7% EtOAc/hexanes) to obtain 98 mg (40%) of the title compound.

Step b:[(1S,2S,4R)-4-({6-[(4-chlorobenzyl)oxy]pyrimidin-4-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate

The title compound was prepared in a fashion analogous to Example 34,step b and Example 65, step d (followed by TBAF removal of secondarysilyl group) to obtain the title compound. ¹H NMR (CD₃OD, 400 MHz) δ:6.82 (s, 1H), 5.88-5.79 (m, 4H), 4.62 (s, 1H), 3.98-3.95 (bs, 1H), 3.81(s, 2H), 2.84-2.75 (m, 2H), 2.64-2.58 (m, 1H), 1.04-0.91 (m, 1H),0.79-0.72 (m, 1H), 0.63-0.37 (m, 3H) ppm. LC/MS: R_(t)=8.62 min, ES+ 430(FA long).

Example 42N-({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl)sulfamide(Compound I-82) Step a: tert-butyl(aminosulfonyl)({(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)-oxy]cyclopentyl}methyl)carbamate

To a solution of{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol(105.3 mg, 0.0002168 mol), N-Boc-sulfonamide (58.9 mg, 0.000300 mol) andtriphenylphosphine (85.3 mg, 0.000325 mol) in EtOAc (4.15 mL) under anatmosphere of nitrogen was added diethyl azodicarboxylate (51.9 μL,0.000330 mol). The mixture was stirred for four hours. The solvent wasremoved and the orange residue was purified by flash chromatography (10to 50% EtOAc/hexanes) to obtain 135.2 mg (94%) of the title compound.

Step b: tert-butyl(aminosulfonyl)({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl)carbamate

To a solution of tert-butyl(aminosulfonyl)({(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]cyclopentyl}methyl)carbamate(331.5 mg, 0.0004094 mol) in THF (1.84 mL, 0.0228 mol) and pyridine(1.84 mL) at 0° C. was added pyridine hydrofluoride (0.25 mL, 0.0028mol) dropwise. The mixture was allowed to slowly warm to 23° C. andstirred for 19 hours. To the reaction was added pyridine hydrofluoride(0.25 mL, 0.0028 mol) and the mixture was stirred an additional 6 hours.The reaction was quenched by the dropwise addition of saturated aqueousNaHCO₃. The mixture was partitioned with additional saturated aqueousNaHCO₃ and EtOAc, separated, and the aqueous was extracted with EtOAc(2×) and CH₂Cl₂ (2×). The combined organics were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography (30 to 70% EtOAc/hexanes) to collect 34.5 mg(15%) of the title compound. LC/MS: R_(t)=1.64 min, ES+ 550 (FAstandard).

Step c:N-({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methyl)sulfamide

To a solution of tert-butyl(aminosulfonyl)({(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}-methyl)carbamate(34.5 mg, 0.0000628 mol) in CH₂Cl₂ (1.4 mL) was added trifluoroaceticacid (0.70 mL, 0.0091 mol) and the mixture was stirred for 15 minutes.The mixture was diluted with toluene and evaporated to dryness. Theresidue was purified by flash chromatography (0 to 10% MeOH/CH₂Cl₂) toobtain 23.8 mg (84%) of the title compound as a white residue. ¹H NMR(CD3OD, 400 MHz) δ: 8.15 (s, 1H), 7.24-7.14 (m, 4H), 5.98 (s, 1H), 5.57(bs, 1H), 5.29 (bs, 1H), 4.38-4.35 (m, 1H), 4.23-4.20 (m, 1H), 3.34 (s,3H), 3.25-3.20 (m, 1H), 3.13-3.00 (m, 3H), 2.42-2.33 (m, 1H), 2.29-2.24(m, 1H), 2.10-1.94 (m, 3H) ppm. LC/MS: R_(t)=1.16 min, ES+ 450 (FAstandard).

Example 43[(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-6-methyl-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-45) Step a:4-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazin-2-amine

To a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.90 g, 0.0055mol) in DMF (3.50 mL) and toluene (1.5 mL) at 0° C. was added(S)-(+)-1-aminoindan (0.64 mL, 0.0050 mol) followed by DIPEA (0.991 mL,0.00569 mol). The mixture was stirred at 0° C. for 30 min. The reactionwas poured into water and extracted with CH₂Cl₂. The organic layer wasdried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography (0 to 15% EtOAc/hexanes) to afford 0.69 g (53%) ofthe title compound.

Step b:N-[(3aS,4R,6S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-N′-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazine-2,4-diamine

A mixture of(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine(141.8 mg, 0.0004703 mol),4-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazin-2-amine(127.1 mg, 0.0004876 mol) and potassium carbonate (0.130 g, 0.000940mol) in 1,4-dioxane (0.77 mL) was subjected to microwave irradiation(300 watts, 160° C.) for 30 minutes. The mixture was filtered withCH₂Cl₂ and concentrated. The residue was purified by flashchromatography (10 to 100% EtOAc/hexanes) to obtain 60 mg (24%) of thetitle compound. LC/MS: R_(t)=2.03 min, ES+ 279 (FA standard).

Step c:[(3aR,4R,6R,6aS)-6-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-6-methyl-1,3,5-triazin-2-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methanol

To a solution ofN-[(3aS,4R,6S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-N′-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methyl-1,3,5-triazine-2,4-diamine(0.23 g, 0.00044 mol) in THF (1 mL) was added 1.00 M of TBAF in THF(1.31 mL). The reaction was stirred for 30 minutes. The solution wasconcentrated and the residue purified by flash chromatography (0 to 4%MeOH/EtOAc) to afford 210 mg (>99%) of the title compound. LC/MS:R_(t)=1.24 min, ES+ 412 (FA standard).

Step d:[(1R,2R,3S,4R)-4-({4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-6-methyl-1,3,5-triazin-2-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate

The title compound was prepared in a fashion analogous to Example 65,step d. ¹H NMR (CD₃OD, 400 MHz) δ: 7.29-7.16 (m, 4H), 5.65 (t, J=7.5 Hz,1H), 4.35 (dd, J=7.7, 14.9 Hz, 1H), 4.14 (s, 1H), 3.92-3.84 (m, 1H),3.10-3.00 (m, 1H), 2.95-2.84 (m, 1H), 2.63-2.52 (m, 1H), 2.35-2.33 (m,2H), 2.30 (s, 3H), 2.08-1.90 (m, 1H), 1.39-1.28 (m, 1H) ppm. LC/MS:R_(t)=1.13 min, ES+ 451 (FA standard).

Example 44{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)amino]cyclopentyl}methylsulfamate (Compound I-47) Step d:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]-6-chloropyrimidin-4-amine

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine(0.400 g, 1.11 mmol) in EtOH (3.0 mL) was added 4,6-dichloro-pyrimidine(0.199 g, 1.33 mmol) and Et₃N (0.310 mL, 2.22 mmol). The reaction washeated to 140° C. for 1 h in a sealed tube using microwave irradiationthen concentrated in vacuo. The residue was dissolved in CH₂Cl₂ andpurified by flash chromatography (CH₂Cl₂) to afford the title compound(0.300 g, 57%).

Step b:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-pyrimidine-4,6-diamine

A mixture ofN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloropyrimidin-4-amine(0.114 g, 2.42 mmol), (1R,2S)-2-methoxyindan-1-amine (0.170 g, 1.04mmol) and Na₂CO₃ (0.10 g, 0.97 mmol) was heated to 180° C. for 2 h in asealed tube using an oil bath. The reaction was cooled and filtered. Thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (50 to 60% EtOAc/hexanes) to afford the title compound asa beige foam (0.066 g, 46%). LC/MS: R_(t)=2.20 min, ES⁺ 599 (FormicAcid).

Step c:{(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol

To a solution ofN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-N′-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidine-4,6-diamine(0.188 g, 0.314 mmol) in THF (1.70 mL) and H₂O (1.70 mL) was added AcOH(5.08 mL). The solution was stirred overnight then concentrated in vacuoand purified by flash chromatography (0 to 5% MeOH/EtOAc) to obtain thetitle compound (0.112 g, 74%). LC/MS: R_(t)=1.46 min, ES⁺ 485 (FormicAcid).

Step d:{(1R,2R,4S)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)amino]cyclopentyl}methylsulfamate (Compound I-47)

A solution of{(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]cyclopentyl}methanol(0.112 g, 0.231 mmol) (azetroped with toluene) and pyridine (0.0374 mL,0.462 mmol) in anhydrous acetonitrile (2.3 mL) was cooled to 0° C. A 2 Nsolution of chlorosulfonamide in acetonitrile (0.116 mL) was addeddropwise and the reaction was stirred for 3 h. Additional 2 N solutionof chlorosulfonamide in acetonitrile (0.026 mL) and pyridine (0.0041 g,0.052 mol) were added and the reaction was stirred for 1 h then quenchedwith methanol. The solution was concentrated in vacuo and purified byflash chromatography (0 to 10% MeOH/DCM) to afford the title compound asa white solid (0.059 g, 57%). ¹H NMR (CD₃OD, 400 MHz, δ): 8.26 (s, 1H);8.01 (s, 1H); 7.26-7.16 (m, 3H); 5.70 (s, 1H); 5.47-5.33 (bs, 1H); 4.35(t, J=4.5 Hz, 1H); 4.31 (d, J=7.5 Hz, 1H); 4.28 (d, J=7.5 Hz, 1H);4.25-4.21 (m, 1H); 4.15-4.11 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 3.36 (s, 3H);3.16-3.00 (m, 2H); 2.54-2.45 (m, 1H); 2.26-2.19 (m, 1H); 2.10-1.98 (m,1H); 1.87-1.78 (m, 1H); 1.77-1.69 (m, 1H). LC/MS: R_(t)=1.11 min, ES⁺450 (FA standard).

Example 45{(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-124)

The title compound was prepared in a fashion analogous to Example 34steps a-e using (1S)-3,3-dimethylindan-1-amine in step b to obtain thetitle compound. ¹H NMR (CD₃OD, 400 MHz, δ): 8.14 (s, 1H); 7.28-7.15 (m,4H); 5.83 (s, 1H); 5.59 (bs, 1H); 5.31 (bs, 1H); 4.39 (dt, J=5.0 Hz;J=2.0 Hz, 1H); 4.32 (dd, J=7.3 Hz; J=2.5 Hz, 1H); 4.16 (dd, J=7.3 Hz;J=2.5 Hz, 1H); 2.57-2.47 (m, 1H); 2.46-2.39 (m, 1H); 2.31-2.24 (m, 1H);2.12-1.90 (m, 3H); 1.82-1.75 (m, 1H); 1.39 (s, 3H); 1.25 (s, 3H). LC/MS:R_(t)=1.51 min, ES⁺ 449 (FA standard).

Example 46{(1S,2S,4R)-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-134) Step a:4,6-dichloro-N-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine

To a solution of (1S)-3,3-dimethylindan-1-amine (0.67 g, 4.2 mmol) inTHF (3 mL) cooled to 0° C. was added cyanuric chloride (0.874 g, 4.74mmol) resulting in a white solid. DIPEA (0.724 mL, 4.16 mmol) was addedand the yellow mixture was stirred for 1.5 hours. The reaction wasquenched with H₂O and extracted with DCM (3×). The combined organiclayers were dried (Na₂SO₄), filtered and collected in vacuo to give apale yellow oil. The residue was purified by flash chromatography (0 to25% EtOAc/hexanes) to afford the title compound (0.771 g, 60%) as awhite solid. LC/MS: R_(t)=2.20 min, ES⁺ 310 (FA standard).

Step b:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-6-chloro-N′-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine(0.200 g, 0.556 mmol), TEA (0.21 mL, 1.50 mmol) in THF (0.80 mL) wasadded4,6-dichloro-N-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine(0.160 g, 0.500 mol). The reaction was stirred for 3.5 h thenconcentrated in vacuo. The residue was purified by preparative TLC (10%EtOAc/hexanes) followed by DCM. The relevant band was cut and washedusing acetone, filtered, and concentrated in vacuo to afford the titlecompound (0.228 g, 71%). LC/MS: R_(t)=2.77 min, ES⁺ 633 (FA standard).

Step c:{(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-chloro-6-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methanol

The title compound was prepared following the procedure described inExample 44 step c usingN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloro-N′-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazine-2,4-diamine.LC/MS: R_(t)=2.20 min, ES⁺ 518, 520 (FA standard).

Step d:{(1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methanol

To a solution of{(1R,2R,4S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-chloro-6-{[(1R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}-methanol(0.083 g, 0.16 mmol) in EtOH (1.11 mL) was added Pd (10% on carbon)(0.0170 g, 0.0160 mmol) and the mixture was stirred under an atmosphereof hydrogen for 4 d. The reaction was purged with nitrogen for 30minutes then Pd(OH)₂ (20% on carbon dry weight) (0.022 g, 0.016 mmol)was added and the mixture was stirred for 4 h under an atmosphere ofhydrogen. Filtration of the mixture through a pad of celite, followed byflash chromatography (50-100% EtOAc/hexanes) afforded the title compound(0.027 g, 35%). LC/MS: R_(t)=1.81 min, ES⁺ 484 (FA standard).

Step e:{(1S,2S,4R)-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl)methylsulfamate (Compound I-134)

The title compound was prepared following the procedure described inExample 44 step d using{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methanol.¹H NMR (CD₃OD, 400 MHz, δ): 8.17-7.81 (m, 1H); 7.27-7.15 (m, 4H);5.71-5.57 (m, 1H); 4.65-4.49 (m, 1H); 4.36-4.23 (m, 2H); 4.20-4.00 (m,1H); 2.53-2.33 (m, 2H); 2.25-2.10 (m, 1H); 2.06-1.68 (m, 4H); 1.39 (s,3H); 1.24 (s, 3H). LC/MS: R_(t)=1.90 min ES⁺ 449 (FA standard).

Example 47{(1R,2R,3S,4R)-2,3-dihydroxy-4-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]cyclopentyl}methylsulfamate (Compound I-55)

The title compound was prepared following the procedure described inExample 46 (step e) using{(3aR,4R,6R,6aS)-6-[(4-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(prepared as in Example 26). ¹H NMR (CD₃OD, 400 MHz, δ): 8.10-7.95 (m,1H); 7.30-7.14 (m, 4H); 5.72-5.56 (m, 1H); 4.36-4.08 (m, 4H); 3.95-3.78(m, 2H); 3.37 (s, 3H); 3.15-2.93 (m, 2H); 2.42-2.17 (m, 2H); 1.37-1.78(m, 1H). LC/MS: R_(t)=1.07 min ES⁺ 467 (FA standard).

Example 48((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(phenylethynyl)pyrimidin-4-yl]amino}-cyclopentyl)methylsulfamate (Compound I-108) Step a:(1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol

To a solution of(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol.HCl (1.00g, 5.44 mmol) and 2-amino-4,6-dichloropyrimidine (0.982 g, 5.99 mmol) inisopropyl alcohol (8 mL) was added Et₃N (1.90 mL, 13.6 mmol). Thereaction was heated to 90° C. for 1 h in an oil bath then cooled,filtered and concentrated in vacuo. The residue was dissolved in CH₂Cl₂and purified by flash chromatography (20 to 50% MeOH/CH₂Cl₂) to affordthe title compound as an off-white solid (2.025 g, >99%). LC/MS:R_(t)=0.81 min ES⁺ 260 (FA standard).

Step b:(1S,2R,3R,5R)-3-(hydroxymethyl)-5-[(6-iodopyrimidin-4-yl)amino]cyclopentane-1,2-diol

To a solution of(1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol(1.880 g, 7.239 mmol) in hydroiodic acid (23.9 mL) was added sodiumiodide (5.42 g, 36.2 mmol). The mixture heated to 70° C. for 10 min thenconcentrated and azeotroped using toluene (3×). The residue wasdissolved in acetone and NaHCO₃ was added. The suspension was filteredand the filtrate was concentrated in vacuo to obtain the title compound(24 g, >99%). LC/MS: R_(t)=0.76 min ES⁺ 352 (FA standard).

Step c:{(3aR,4R,6R,6aS)-6-[(6-iodopyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

The title compound was prepared following the procedure described inExample 1 step b using(1S,2R,3R,5R)-3-(hydroxymethyl)-5-[(6-iodopyrimidin-4-yl)-amino]cyclopentane-1,2-diol.LC/MS: R_(t) 1.24 min ES⁺ 392 (FA standard).

Step d:N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-iodopyrimidin-4-amine

To a solution of{(3aR,4R,6R,6aS)-6-[(6-iodopyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(1.321 g, 3.38 mmol) and 1H-imidazole (0.552 g, 8.10 mmol) in DMF (16.9mL) was added tert-butyldimethylsilyl chloride (0.534 g, 3.54 mmol) andthe reaction was stirred overnight. The solution was diluted with H₂Oand extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude mixture was purified by flash chromatography (10 to 40%EtOAc/hexanes) to afford the title compound (1.465 g, 86%). LC/MS:R_(t)=2.47 min ES⁺ 506 (FA Standard).

Step e:N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-(phenylethynyl)-pyrimidin-4-amine

To a solution ofN-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-iodopyrimidin-4-amine(0.300 g, 0.594 mmol) in DMF (2.46 mL) was added CuI (0.0113 g, 0.0594mmol) and bis(triphenylphosphine)palladium(II) chloride (0.0292 g,0.0415 mmol). The tube was sealed and flushed with argon. Et₃N (0.165mL, 1.19 mol) was added and the reaction was stirred for 1 h.Phenylacetylene (0.216 mL, 1.96 mmol) was added and the reaction wasstirred overnight. The suspension was filtered and the filtrate wasconcentrated in vacuo. The crude mixture was purified by flashchromatography (10 to 40% EtOAc/hexanes) to afford the title compound asa yellow oil (0.238 g, 84%). LC/MS: R_(t)=2.47 min, ES⁺ 480 (FAstandard).

Step f:((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(phenylethynyl)pyrimidin-4-yl]amino}-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

To a solution ofN-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-(phenylethynyl)pyrimidin-4-amine(0.275 g, 0.573 mmol) in THF (2 mL) and pyridine (2 mL) in a teflon vialwas added pyridine hydrofluoride (1.3 mL, 0.014 mol) dropwise. Thereaction was stirred for 1.5 h then quenched using a saturated aqueousNa₂CO₃ solution (15 mL) and EtOAc. The aqueous layer was extracted withEtOAc (3×20 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by flashchromatography (0 to 5% MeOH/EtOAc) to afford the title compound as ayellow solid (0.172 g, 82%). LC/MS: R_(t)=1.29 min, ES⁺ 366 (FAstandard).

Step g:((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(phenylethynyl)pyrimidin-4-yl]amino}-cyclopentyl)methylsulfamate (Compound I-108)

The title compound was prepared following the procedure described inExample 1 steps d-e using((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(phenylethynyl)pyrimidin-4-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.¹H NMR (CD₃OD, 400 MHz, δ): 8.36 (s, 1H); 7.80-7.54 (m, 2H); 7.45-7.38(m, 3H); 6.69 (bs, 1H); 4.33 (bs, 1H); 4.23-4.14 (m, 2H); 3.92-3.88 (m,1H); 3.86-3.81 (m, 1H); 3.32-3.28 (m, 2H); 2.46-2.30 (m, 2H); 1.39-1.27(m, 1H). LC/MS: R_(t)=1.09 min, ES⁺ 405 (FA standard).

Example 49[(1S,2S,4R)-2-hydroxy-4-({6-[(1-naphthylmethyl)amino]pyrimidin-4-yl}-oxy)cyclopentyl]methylsulfamate (Compound I-42)

The title compound was prepared in a fashion analogous to Example 34steps a-e using 1-naphthalenemethylamine in step b to obtain the titlecompound. ¹H NMR (CD₃OD, 400 MHz, δ): 8.13 (s, 1H); 8.04 (d, J=9.0 Hz,1H); 7.87 (d, J=7.5 Hz, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.54-7.39 (m, 5H);5.75 (s, 1H); 5.31-5.26 (m, 1H); 4.94 (s, 2H); 4.39-4.25 (m, 2H);4.17-4.06 (m, 1H); 2.52-2.42 (m, 1H); 2.26-2.19 (m, 1H); 2.05-1.84 (m,2H). LC/MS: R_(t)=1.59 min, ES⁺ 445 (FA standard).

Example 50[(1S,2S,4R)-2-hydroxy-4-({6-[(1-naphthylmethyl)amino]pyrimidin-4-yl}-oxy)cyclopentyl]methylsulfamate (Compound I-119) Step a:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-(1-naphthylmethoxy)pyrimidine

To a solution of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(0.200 g, 0.423 mmol) and 1-naphthalenemethanol (0.140 g, 0.888 mmol) inDMF (1 mL) was added sodium hydride (0.0355 g, 0.888 mmol) and stirredfor 3 h. The mixture was diluted with H₂O and extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified by flashchromatography (0 to 20% EtOAc/hexanes) to afford the title compound(0.139 g, 55%).

Step b:[(1S,2S,4R)-2-hydroxy-4-({6-[(1-naphthylmethyl)amino]pyrimidin-4-yl}-oxy)cyclopentyl]methylsulfamate

The title compound was prepared following the procedure described inExample 44 (steps c-d) and Example 48 (step f) using4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)-silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-(1-naphthylmethoxy)pyrimidine.¹H NMR (CD₃OD, 400 MHz, δ): 8.39 (s, 1H); 8.01 (d, J=8.8 Hz, 1H);7.88-7.81 (m, 2H); 7.57 (d, J=7.0 Hz, 1H); 7.53-7.40 (m, 3H); 6.14 (s,1H); 5.79 (s, 2H); 5.50-5.42 (m, 1H); 4.35-4.31 (m, 1H); 4.30-4.25 (m,1H); 4.15-4.03 (m, 1H); 2.53-2.42 (m, 1H); 2.30-2.21 (m, 1H); 2.08-1.87(m, 3H). LC/MS: R_(t)=1.82 min, ES⁺ 446 (FA standard).

Example 51((1S,2S,4R)-2-hydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}-cyclopentyl)methylsulfamate (Compound I-81) Step a:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-6-iodopyrimidin-4-amine

The title compound was prepared following the procedure described inExample 44 step a using 4,6-diiodopyrimidine heating to 150° C. for 300sec.

Step b:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-6-(phenylethynyl)pyrimidin-4-amine

The title compound was prepared following the procedure described inExample 48 step e. LC/MS: R_(t)=3.56 min, ES⁺ 538 (FA standard).

Step c:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-6-(2-phenylethyl)pyrimidin-4-amine

The title compound was prepared following the procedure described inExample 3d usingN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]-6-(phenylethynyl)pyrimidin-4-amineand Pd(OH)₂ on carbon (20% dry weight). LC/MS: R_(t)=2.30 min, ES⁺ 542(FA standard).

Step d:((1S,2S,4R)-2-hydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}cyclopentyl)-methylsulfamate (Compound I-81)

The title compound was prepared following the procedure described inExample 46 steps c and e and Example 48 step f. ¹H NMR (CD₃OD, 400 MHz,δ): 8.30 (s, 1H); 7.26-7.20 (m, 2H); 7.18-7.13 (m, 3H); 6.18 (s, 1H):4.35-4.26 (m, 2H); 4.15-4.06 (m, 1H); 2.97-2.90 (m, 2H); 2.85-2.76 (m,2H); 2.51-2.41 (m, 1H); 2.24-2.15 (m, 1H); 1.82-1.73 (m, 1H); 1.70-1.60(m, 1H); 0.94-0.85 (m, 1H). LC/MS: R_(t)=1.38 min, ES⁺ 393 (FAstandard).

Example 52((1S,2S,4R)-2-hydroxy-4-{[6-(2-naphthylmethoxy)pyrimidin-4-yl]oxy}-cyclopentyl)methylsulfamate (Compound I-141)

The title compound was prepared following the procedure described inExample 50 using 2-naphthalenemethanol. ¹H NMR (CD₃OD, 400 MHz, δ): 8.39(s, 1H); 7.88 (s, 1H); 7.86-7.81 (m, 3H); 7.52 (dd, J=8.5 Hz, J=1.76 Hz,1H); 7.49-7.44 (m, 2H); 6.19 (s, 1H); 5.53-5.48 (m, 1H); 4.38-4.35 (m,1H); 4.34-4.29 (m, 1H); 4.17-4.12 (m, 1H); 2.56-2.46 (m, 1H); 2.32-2.26(m, 1H); 2.09-1.91 (m, 3H). LC/MS: R_(t)=1.82 min ES⁺ 446 (FA standard).

Example 53{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-96) Step a:(1R,2S)-1-[(6-chloropyrimidin-4-yl)oxy]indan-2-ol and(1R,2S)-2-[(6-chloropyrimidin-4-yl)oxy]indan-1-ol

The title compounds were prepared following the procedure described inExample 34 step a using (1R,2S)-indane-1,2-diol (0.5 g, 3.00 mmol)(Yanagimachi, K. S; Stafford, D; Dexter, A; Sinskey, A; Drew, S;Stephanopoulos, G. European Journal of Biochemistry. 2001, 268,4950-4960) as a 1.2:1 ratio of 2-O-pyrimidine to 1-O-pyrimidine.

Step b:4-chloro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}pyrimidineand4-chloro-6-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}pyrimidineand4-chloro-6-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}pyrimidine

To a flame dried flask containing 4 Å molecular sieves (0.700 g) cooledunder nitrogen and equipped with a reflux condenser was added silver(I)oxide (3 g, 10.0 mmol),(1R,2S)-1-[(6-chloropyrimidin-4-yl)oxy]indan-2-ol (0.365 g, 1.39 mmol),and Et₂O (10 mL). MeI (3.08 mL, 49.5 mmol) was pre-purified through analumina plug and added to the mixture. The reaction was heated to 40° C.for 2 h. The reaction was diluted with Et₂O, filtered through a pad ofcelite and concentrated in vacuo. The residue was purified by flashchromatography (15 to 30% EtOAc/hexanes) to obtain the title compoundsas a 1:1 mixture (0.540 g, 70%).

Step c:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidine,andtert-butyl{[(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}phenoxy)cyclopentyl]-methoxy}dimethylsilane,and4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}pyrimidine,andtert-butyl{[(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[(1S,2R)-1-methoxy-2,3-dihydro-1H-inden-2-yl]-oxy}phenoxy)cyclopentyl]methoxy}dimethylsilane

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(0.334 g, 0.928 mmol) and sodium hydride (0.0779 g, 1.95 mmol) in DMF (3mL) was added4-chloro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}pyrimidine(0.539 g, 1.95 mmol). The mixture was stirred for 5 h then quenched withH₂O and extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (MgSO₄) and concentrated in vacuo. The residuewas purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtainthe title compounds (0.124 g, 22%).

Step d:{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}-pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate, and{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}pyrimidin-4-yl)-oxy]cyclopentyl}methylsulfamate, and{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate, and{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compounds I-96, I-79, I-98, I-77)

The title compounds were prepared using the procedure described inExample 51 step d using4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}-pyrimidine,andtert-butyl{[(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}phenoxy)cyclopentyl]methoxy}dimethylsilane,and4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]oxy}pyrimidine,andtert-butyl{[(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[(1S,2R)-1-methoxy-2,3-dihydro-1H-inden-2-yl]oxy}phenoxy)cyclopentyl]methoxy}dimethylsilane.

Example 54{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-96)

¹H NMR (CD₃OD, 400 MHz, δ): 8.44 (s, 1H); 7.45 (d, J=7.3 Hz, 1H);7.32-7.25 (m, 2H); 7.23-7.17 (m, 1H); 6.53 (d, J=5.0 Hz, 1H); 6.12 (s,1H); 5.52-5.47 (m, 1H); 4.39-4.36 (m, 1H); 4.35-4.27 (m, 2H); 4.14 (dd,J=9.8 Hz, J=2.5 Hz, 1H); 3.37 (s, 3H); 3.20-3.06 (m, 2H); 2.56-2.47 (m,1H); 2.34-2.25 (m, 1H); 2.11-1.89 (m, 3H). LC/MS: R_(t)=1.64 min, ES⁺452 (FA standard).

Example 55{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-1-methoxy-2,3-dihydro-1H-inden-2-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-79)

¹H NMR (CD₃OD, 400 MHz, δ): 8.40 (s, 1H); 7.40 (d, J=7.3 Hz, 1H);7.33-7.23 (m, 3H); 6.13 (s, 1H); 5.78 (q, J=5.77 Hz, J=5.52 Hz, 1H);5.54-5.47 (m, 1H); 4.94 (d, J=4.77 Hz, 1H); 4.41-4.36 (m, 1H); 4.35-4.29(m, 1H); 4.18-4.12 (m, 1H); 3.38 (s, 3H); 3.28-3.23 (m, 1H); 3.20-3.12(m, 1H); 2.57-2.47 (m, 1H); 2.33-2.25 (m, 1H); 2.10-1.90 (m, 3H). LC/MS:R_(t)=1.64 min, ES⁺ 452 (FA standard).

Example 56{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-98)

¹H NMR (CD₃OD, 400 MHz, δ): 8.44 (s, 1H); 7.45 (d, J=7.5 Hz, 1H);7.32-7.25 (m, 2H); 7.23-7.16 (m, 1H); 6.53 (d, J=5.0 Hz, 1H); 6.12 (s,1H); 5.53-5.47 (m, 1H); 4.40-4.35 (m, 1H); 4.34-4.27 (m, 2H); 4.15 (dd,J=7.3 Hz, J=5.1 Hz, 1H); 3.37 (s, 3H); 3.19-3.06 (m, 2H); 2.56-2.47 (m,1H); 2.33-2.25 (m, 1H); 2.10-1.90 (m, 3H). LC/MS: R_(t)=1.65 min, ES⁺452 (FA standard).

Example 57{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-1-methoxy-2,3-dihydro-1H-inden-2-yl]-oxy}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-77)

¹H NMR (CD₃OD, 400 MHz, δ): 8.40 (s, 1H); 7.41 (d, J=7.0 Hz, 1H);7.33-7.23 (m, 3H); 6.13 (s, 1H); 5.81-5.76 (m, 1H); 5.55-5.48 (m, 1H);4.94 (d, J=5.0 Hz, 1H); 4.41-4.36 (m, 1H); 4.32 (dd, J=9.8 Hz; J=2.3 Hz,1H); 4.15 (dd, J=9.8 Hz; J=2.5 Hz, 1H); 3.38 (s, 3H); 3.28-3.22 (m, 1H);3.20-3.12 (m, 1H); 2.57-2.47 (m, 1H); 2.33-2.26 (m, 1H); 2.10-1.93 (m,3H). LC/MS: R_(t)=1.64 min, ES⁺ 452 (FA Standard).

Example 58{(1S,2S,4R)-2-hydroxy-4-[(6-phenylpyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-114) Step a:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-phenylpyrimidine

A flask containing4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(0.300 g, 0.634 mmol), phenylboronic acid (0.0696 g, 0.570 mmol), a 2.00M solution of K₂CO₃ in H₂O (0.317 mL), EtOH (0.0944 mL) and toluene(1.417 mL) was purged with argon for 20 minutes.Tetrakis(triphenylphosphine)palladium(0) (0.0264 g, 0.0229 mmol) wasadded and the mixture was refluxed overnight. The reaction was cooledand diluted with H₂O. The aqueous layer was extracted with CH₂Cl₂ (3×).The combined organics were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatography(0 to 10% EtOAc/hexanes) to afford the title compound (0.224 g, 76%).

Step b:{(1S,2S,4R)-2-hydroxy-4-[(6-phenylpyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-114)

The title compound was prepared as described in Example 46 steps c and eand Example 48 step f using4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-phenylpyrimidine.¹H NMR (CD₃OD, 400 MHz, δ): 8.73 (s, 1H); 8.03-7.98 (m, 2H); 7.51-7.47(m, 3H); 7.21 (s, 1H); 5.70-5.65 (m, 1H); 4.44-4.39 (m, 1H); 4.35 (dd,J=7.5 Hz, J=2.3 Hz, 1H); 4.17 (dd, J=7.3 Hz, J=2.5 Hz, 1H); 3.30 (q,J=3.3 Hz, J=1.6 Hz, 1H); 2.62-2.51 (m, 1H); 2.38-2.30 (m, 1H); 2.17-1.96(m, 3H). LC/MS: R_(t)=1.55 min, ES⁺ 366 (FA standard).

Example 59{(1S,2S,4R)-4-[(6-benzylpyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-132) Step a:4-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]oxy}pyrimidine

To a solution of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine(0.264 g, 0.559 mmol) and ferric acetylacetonate (0.0395 g, 0.112 mmol)in THF (9 mL) was added a 1.00 M solution of benzylmagnesium bromide inTHF (2.52 mL) and the mixture was stirred overnight. The reaction wasquenched using NH₄Cl and extracted with EtOAc (3×). The combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (0 to 15% EtOAc/hexanes) toafford the title compound as a clear oil. (0.254 g, 86%).

Step b:{(1S,2S,4R)-4-[(6-benzylpyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-132)

The title compound was prepared as described in Example 46 steps c and eand Example 48 step f using4-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}pyrimidine.¹H NMR (CD₃OD, 400 MHz, δ): 8.69 (s, 1H); 7.38-7.22 (m, 6H); 6.41 (s,1H); 5.65-5.58 (m, 1H); 4.52-4.47 (m, 1H); 4.45-4.39 (m, 1H); 4.31-4.25(m, 1H); 4.03 (s, 2H); 2.63-2.53 (m, 1H); 2.37-2.28 (m, 1H); 2.16-1.84(m, 4H). LC/MS: R_(t)=1.42 min, ES⁺ 380 (FA standard).

Example 60((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}-cyclopentyl)methylsulfamate (Compound I-86) Step a:((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol

The title compound was prepared following the procedure described inExample 46 step d using((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(phenylethynyl)pyrimidin-4-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.

Step b:((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(2-phenylethyl)pyrimidin-4-yl]amino}-cyclopentyl)methylsulfamate (Compound I-86)

The title compound was prepared following the procedure described inExample 48 step g using((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(2-phenylethyl)pyrimidin-4-yl]-amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol.¹H NMR (CD₃OD, 400 MHz, δ): 8.45 (s, 1H); 7.30-7.16 (m, 5H); 6.41 (bs,1H); 4.41 (bs, 1H); 4.19-4.12 (m, 2H); 3.90-3.85 (m, 1H); 3.83-3.78 (m,1H); 3.38 (s, 2H); 3.03-2.86 (m, 4H); 2.41-2.29 (m, 2H); 1.37-1.26 (m,1H). LC/MS: R_(t)=0.99 min, ES⁺ 409 (FA standard).

Example 61[(1S,3R,4R)-3-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-4-hydroxycyclopentyl]methylsulfamate (Compound I-76) Step a:(1R,2R,4R)-2-amino-4-(hydroxymethyl)cyclopentanol

A solution of (1R,3R,5S)-6-oxabicyclo[3.1.0]hex-3-ylmethanol (0.419 g,3.67 mmol) (Feeya, David. Journal of Organic Chemistry, 1981, 46,3512-3519) in ammonium hydroxide (7.22 mL) was heated to 65° C.overnight. The solution was concentrated in vacuo and azeotroped withtoluene (3×) to afford the title compound as a clear oil (0.473 g, 98%).

Step b:1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentanol

The title compound was prepared following the procedure described inExample 48 steps c-d using(1R,2R,4R)-2-amino-4-(hydroxymethyl)cyclopentanol.

Step c:(1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentylacetate

To a solution of(1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentanol(0.193 g, 0.424 mmol), N,N-dimethylaminopyridine (4.7 mg, 0.039 mmol)and pyridine (0.281 mL, 3.48 mmol) in DCM (2.1 mL) was added aceticanhydride (0.044 mL, 0.46 mmol) and the mixture stirred overnight. Thereaction was diluted with CH₂CL₂ (10 mL) and H₂O (20 mL) then stirredfor 10 m. The organic layer was separated and the aqueous layer wasextracted with CH₂CL₂ and combined organics were washed with H₂O. Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo toobtain the title compound. LC/MS: R_(t)=1.74 min, ES⁺ 498 (FA Standard).

Step d:[(1S,3R,4R)-3-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-4-hydroxycyclopentyl]methylsulfamate (Compound I-76)

The title compound was prepared following the procedure described inExample 57 step d using(1R,2R,4R)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)cyclopentylacetate. ¹H NMR (CD₃OD, 400 MHz, δ): 7.95 (s, 1H); 7.28-7.14 (m, 4H);5.66-5.61 (m, 1H); 5.30 (bs, 1H); 4.07 (s, 1H); 4.05 (s, 1H); 4.02 (q,J=5.3 Hz, 1H); 3.82 (bs, 1H); 3.05-2.96 (m, 1H); 2.92-2.82 (m, 1H);2.63-2.52 (m, 2H); 2.41-2.30 (m, 1H); 1.39-1.28 (m, 1H). LC/MS:R_(t)=0.94 min, ES⁺ 420 (FA standard).

Example 62[(1R,3R,4R)-3-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-amino)-4-hydroxycyclopentyl]methylsulfamate (Compound I-58)

The title compound was prepared following the procedure described inExample 59 steps a-d using(1S,2S,4R)-2-amino-4-(hydroxymethyl)cyclopentanol. ¹H NMR (CD₃OD, 400MHz, δ): 7.95 (s, 1H); 7.29-7.13 (m, 5H); 5.61 (d, J=5.0 Hz, 1H); 5.30(bs, 1H); 4.08 (s, 1H); 4.06 (s, 1H); 4.01 (q, J=6.3 Hz, 1H); 3.82 (bs,1H); 3.04-2.95 (m, 1H); 2.92-2.83 (m, 1H); 2.61-2.46 (m, 2H); 2.25-2.17(m, 1H); 2.06-1.96 (m, 1H); 1.93-1.82 (m, 1H); 1.80-1.70 (m, 1H);1.49-1.40 (m, 1H). LC/MS: R_(t)=0.94 min, ES⁺ 420 (FA standard).

Example 63{(1R,2R,3S,4R)-4-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-(methyl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-106) Step a:N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-N-methylpyrimidin-4-amine

To a mixed solution ofN-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloropyrimidin-4-amine(405 mg, 0.98 mmol) in THF (10.0 mL) and DMF (2.50 mL) was added sodiumhydride (47.0 mg, 1.17 mmol) under an atmosphere of Argon, and themixture was stirred for 15 minutes. Methyl iodide (0.08 mL, 1.27 mmol)was added to the mixture, and the resulting mixture was stirred for 1 h.After quenching by addition of brine (20.0 mL), the mixture wasextracted with ethyl acetate (3×40.0 mL). The organic layers werecombined, dried over MgSO₄, filtered, and evaporated under vacuum. Theresidue was purified via silica gel column chromatography eluting with agradient of 5 to 15% ethyl acetate in DCM to afford the title compound(381 mg, 91%) as a colorless oil. LC/MS: R_(t)=2.55 min, ES⁺ 428.3 (AAstandard).

Step b:{(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

To a stirred solution ofN-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-N-methylpyrimidin-4-amine(400 mg, 0.93 mmol) in THF (10.0 mL) was added 1M solution oftetra-n-butylammonium fluoride in THF (1.00 mL, 1.00 mmol), and themixture was stirred for 2 h. After quenching by addition of brine (20.0mL), the resulting mixture was extracted with ethyl acetate (3×40.0 mL).The organic layers were combined, dried over MgSO₄, filtered, andevaporated under vacuum. The residue was purified via silica gel columnchromatography eluting with a gradient of 40 to 100% ethyl acetate inDCM to afford the title compound (261 mg, 89%) as a colorless oil.LC/MS: R_(t)=1.24 min, ES⁺ 314.2 (AA standard).

Step c:{(3aR,4R,6R,6aS)-6-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}-methanol

{(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol(130 mg, 0.41 mmol) was weighed into a microwave reaction tube anddissolved in 1-butanol (1.50 mL). To this solution was addedN,N-diisopropylethylamine (0.22 mL, 1.24 mmol) and (S)-(+)-1-aminoindan(0.16 mL, 1.24 mmol) and the mixture was heated in a sealed tube undermicrowave irradiation at 200° C. for 4 h. The reaction mixture wasconcentrated under vacuum, and the residue was purified via silica gelcolumn chromatography eluting with a gradient of 2 to 5% methanol in DCMto afford the title compound (40.5 mg, 24%) as a colorless oil. LC/MS:R_(t)=1.49 min, ES⁺ 411.5 (AA standard).

Step d:{(3aR,4R,6R,6aS)-6-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methylsulfamate

The title compound was prepared following the procedure described inExample 1 step d. LC/MS: R_(t)=1.68 min, ES⁺ 490.3 (AA standard).

Step e:{(1R,2R,3S,4R)-4-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}(methyl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-106)

To a stirred solution of{(3aR,4R,6R,6aS)-6-[{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methylsulfamate (12.0 mg, 0.02 mmol) in methanol (3.00 mL) was added 1.00 Mhydrochloric acid (0.10 mL), and the mixture was stirred for 8 h. Afterquenching by addition of saturated NaHCO₃ solution, the resultingmixture was evaporated under vacuum. The residue was purified via silicagel column chromatography eluting with a gradient of 5 to 10% methanolin DCM to afford the title compound (7.80 mg, 71%). ¹H-NMR (400 MHz,CD₃OD) δ: 8.01 (s, 1H), 7.27-7.13 (m, 4H), 5.67 (s, 1H), 5.42-5.34 (m,1H), 4.88-4.75 (m, 1H), 4.17 (d, 2H, J=5.6 Hz), 4.04 (dd, 1H, J=8.8, 6.1Hz), 3.88 (dd, 1H, J=5.8, 4.1 Hz), 3.05-2.96 (m, 1H), 2.89 (s, 3H),2.93-2.83 (m, 1H), 2.62-2.52 (m, 1H), 2.34-2.24 (m, 1H), 2.01 (dt, 1H,d=13.0, 8.3 Hz), 1.94-1.83 (m, 1H), 1.44 (ddd, 1H, J=13.0, 10.8, 9.1).LC/MS: R_(t)=5.79 min, ES⁺ 450.2 (AA Waters).

Example 64[(1R,2R,3S,4R)-4-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoropyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-113) Step a:(1R,2S,3R,5R)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diol

The title compound was prepared following the procedure described inExample 1 using 2,4-dichloro-5-fluoropyrimidine in step a. LC/MS:R_(t)=0.89 min, ES⁺ 278.0 (FA standard).

Step b:{(3aR,4R,6R,6aS)-6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol

The title compound was prepared following the procedure described inExample 1 using(1R,2S,3R,5R)-3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diolin step b. LC/MS: R_(t)=1.42 min, ES⁺ 318.1 (FA standard).

Step c:[(3aR,4R,6R,6aS)-6-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoropyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methanol

The title compound was prepared following the procedure described inExample 1 using{(3aR,4R,6R,6aS)-6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanolin step c. LC/MS: R_(t)=1.20 min, ES⁺ 415.6 (FA standard).

Step d:[(1R,2R,3S,4R)-4-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-5-fluoropyrimidin-4-yl}amino)-2,3-dihydroxycyclopentyl]methylsulfamate (Compound I-113)

The title compound was prepared following the procedure described inExample 65 step d. (63.5 mg, 62%) ¹H-NMR (400 MHz, CD₃OD) δ: 8.29 (bs,1H), 7.65 (d, 1H, J=4.6 Hz), 7.29-7.13 (m, 4H), 5.43 (t, 1H, J=7.3 Hz),4.44-4.37 (m, 1H), 4.17 (dd, 1H, J=9.8, 5.1 Hz), 4.13 (dd, 1H, J=9.8,5.3 Hz), 3.93-3.86 (m, 2H), 3.01 (ddd, 1H, J=16.0, 8.8, 3.5 Hz), 2.87(dt, 1H, J=16.0, 8.0 Hz), 2.62-2.53 (m, 1H), 2.35-2.24 (m, 2H),1.98-1.87 (m, 1H), 1.40-1.27 (m, 1H). LC/MS: R_(t)=4.21 min, ES⁺ 454.2(FA long).

Example 65{(1S,2S,4R)-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-83) Step a:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-chloro-5-fluoropyrimidine

To a stirred suspension of sodium hydride (37.4 mg, 0.93 mmol) in THF(5.00 mL) was added a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(285 mg, 0.79 mmol) in THF (2.50 mL) at 0° C. under an atmosphere ofArgon, and the mixture was stirred for 15 minutes. To this cooledsuspension was added a solution of 4,6-dichloro-5-fluoropyrimidine (120mg, 0.72 mmol) in THF (2.50 mL) at 0° C., and the resulting mixture wasstirred for 19 h at 23° C. After quenching by addition of saturatedNH₄Cl solution (50.0 mL), the mixture was extracted with ethyl acetate(3×70.0 mL). The organic layers were combined, dried over MgSO₄,filtered, and evaporated under vacuum. The residue was purified viasilica gel column chromatography eluting with a gradient of 5 to 7%ethyl acetate in hexanes to afford the title compound (295 mg, 79%).¹H-NMR (400 MHz, CDCl₃) δ: 8.32 (s, 1H), 5.67-5.61 (m, 1H), 4.41-4.37(m, 1H), 3.73 (dd, 1H, J=9.8, 7.1 Hz), 3.59 (dd, 1H, J=9.8, 6.6 Hz),2.33-2.25 (m, 1H), 2.10-1.96 (m, 2H), 1.90 (ddd, 1H, J=13.8, 7.7, 1.8Hz), 1.55 (s, 18H), 0.89 (s, 6H), 0.88 (s, 6H).

Step b:6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-5-fluoro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine

4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-6-chloro-5-fluoropyrimidine(260 mg, 0.53 mmol), (1R,2S)-2-methoxyindan-1-amine (364 mg, 2.12 mmol),and sodium carbonate (224 mg, 2.12 mmol) was weighed into a microwavereaction tube. This mixture was heated in a sealed tube under microwaveirradiation at 180° C. for 2 h. The reaction mixture was diluted withDCM (100 mL), and the suspension was filtered. The filtrate was washedwith saturated NH4Cl solution (100 mL), and the organic layer was driedover MgSO₄. This suspension was filtered, and evaporated under vacuum.The residue was purified via silica gel column chromatography elutingwith a gradient of 0 to 10% methanol in DCM to afford the title compound(313 mg, 91%).

Step c:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol

The title compound was prepared following the procedure described inExample 34 using6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]oxy}-5-fluoro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-aminein step c. LC/MS: R_(t)=2.60 min, ES⁺ 504.5 (FA standard).

Step d:{(1S,2S,4R)-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-83)

To a stirred solution of{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino})pyrimidin-4-yl)-oxy]cyclopentyl}methanol(190 mg, 0.36 mmol) in THF (5.40 mL) was added triethylamine (0.08 mL,0.54 mmol) and [(diphenylamino)carbonyl]sulfamoyl chloride (186 mg, 0.54mmol) at 0° C. under an atmosphere of Argon, and the mixture was stirredfor 30 min. The reaction mixture was added 1.00 M Hydrochloric acid in(5.40 mL) at 23° C., and the resulting mixture was stirred for 16 h. Thereaction mixture was quenched by addition of saturated NaHCO₃ solution(80.0 mL) and extracted with ethyl acetate (3×100 mL). The organiclayers were combined, dried over MgSO₄, filtered, and evaporated undervacuum. The residue was purified via silica gel column chromatographyeluting with a gradient of 0 to 10% methanol in DCM to afford the titlecompound (91.0 mg, 51%). ¹H-NMR (400 MHz, CD₃OD) δ: 8.01 (s, 1H),7.25-7.13 (m, 4H), 5.72 (d, 1H, J=6.5 Hz), 5.65-5.58 (m, 1H), 4.43-4.38(m, 1H), 4.33 (dd, 1H, J=9.7, 7.6 Hz), 4.22 (dt, 1H, J=5.0, 2.4 Hz),4.16 (dd, 1H, J=9.7, 7.3 Hz), 3.35 (s, 3H), 3.14 (dd, 1H, J=16.6, 2.4Hz), 3.02 (dd, 1H, J=16.6, 5.0 Hz), 2.60-2.49 (m, 1H), 2.31 (ddd, 1H,d=14.8, 6.8, 2.3 Hz), 2.12 (ddd, 1H, J=14.8, 5.0, 4.7), 2.08-1.95 (m,2H). LC/MS: R_(t)=6.76, ES⁺ 469.3 (FA long).

Example 66{(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-5-fluoropyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-71) Step a:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)sily]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-6-chloro-5-fluoropyrimidin-4-amine

A solution of 4,6-dichloro-5-fluoropyrimidine (102 mg, 0.61 mmol),(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine(200 mg, 0.56 mmol), and triethylamine (0.16 mL, 1.11 mmol) in ethanol(2.00 mL) was heated in a sealed tube under microwave irradiation at140° C. for 1 h. The reaction mixture was concentrated under vacuum, andthe residue was purified by flash chromatography (0 to 15% ethylacetate/hexanes) to afford the title compound (213 mg, 70%) as a lightyellow solid. LC/MS: R_(t)=2.60 min, ES⁺ 490.5 (AA standard).

Step b:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-N′-[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]-5-fluoropyrimidine-4,6-diamine

A mixture ofN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloro-5-fluoropyrimidin-4-amine(205 mg, 0.38 mmol), (1S)-3,3-dimethylindan-1-amine (243 mg, 1.51 mmol),and sodium carbonate (160 mg, 1.51 mmol) was stirred at 180° C. for 3 hin an oil bath. The reaction mixture was diluted with DCM and thesuspension was filtered. The filtrate was concentrated under vacuum andthe residue was purified by flash chromatography (5 to 10% ethylacetate/hexanes) to afford the title compound (213 mg, 70%) as acolorless amorphous solid.

Step c:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-5-fluoropyrimidin-4-yl)amino]cyclopentyl}-methanol

The title compound was prepared following the procedure described inExample 34 step c. LC/MS: R_(t)=2.51 min, ES⁺ 501.5 (AA standard).

Step d:{(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-5-fluoropyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-71)

The title compound was prepared following the procedure described inExample 65 step d. (63.5 mg, 62%). ¹H-NMR (400 MHz, CD₃OD) δ: 7.84 (d,1H, J=1.2 Hz), 7.25-7.15 (m, 4H), 5.68 (dd, 1H, J=8.8, 7.7 Hz), 4.67(ddd, 1H, J=16.3, 8.0, 4.3 Hz), 4.37-4.33 (m, 1H), 4.31 (dd, 1H, J=9.8,7.8 Hz), 4.13 (dd, 1H, J=9.8, 7.1 Hz), 2.58-2.47 (m, 1H), 2.40 (dd, 1H,J=12.3, 7.3 Hz), 2.22 (ddd, 1H, J=13.8, 7.8, 1.8 Hz), 2.04 (ddd, 1H,J=13.5, 10.1, 4.5 Hz), 1.91-1.81 (m, 2H), 1.73 (ddd, 1H, J=13.5, 8.7,4.0 Hz), 1.40 (s, 3H), 1.23 (s, 3H). LC/MS: R_(t)=7.53 min, ES⁺ 466.2(FA long).

Example 67((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)-pyrimidin-4-yl]amino}cyclopentyl)methylsulfamate (Compound I-118) Step a:(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentane-1,2-diol

The title compound was prepared following the procedure described inExample 1 steps a and c using 5,6,7,8-tetrahydro-1-naphthylamine in stepc. LC/MS: R_(t)=1.29 min, ES⁺ 371.3 (AA standard).

Step b:((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-methanol

To a stirred solution of(1S,2R,3R,5R)-3-(hydroxymethyl)-5-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentane-1,2-diol(70.0 mg, 0.19 mmol) in acetone (5.00 mL) was added 2,2-dimethoxypropane(0.21 mL, 1.70 mmol) and pyridinium p-toluenesulfonate (57.0 mg, 0.23mmol), and the mixture was stirred for 55 h. The reaction mixture wasquenched by addition of saturated NaHCO₃ solution (50.0 mL) and thenextracted with ethyl acetate (3×50.0 mL). The organic layers werecombined, dried over MgSO₄, filtered, and evaporated under vacuum. Theresidue was purified by flash chromatography (2 to 10% Methanol/DCM) toafford the title compound (72.0 mg, 85%) as a light yellow amorphoussolid. LC/MS: R_(t)=1.59 min, ES⁺ 411.3 (AA standard).

Step c:((1R,2R,3S,4R)-2,3-dihydroxy-4-{[6-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyrimidin-4-yl]amino}cyclopentyl)methylsulfamate (Compound I-118)

The title compound was prepared following the procedure described inExample 65 step d. ¹H-NMR (400 MHz, CD₃OD) δ: 7.96 (s, 1H), 7.13-7.02(m, 2H), 6.97 (d, 1H, J=7.2 Hz), 5.46 (s, 1H), 4.18-4.08 (m, 2H),4.02-3.87 (m, 1H), 3.85 (dd, 1H, J=5.5, 4.0 Hz), 3.73 (dd, 1H, J=5.8,5.5 Hz), 2.82-2.76 (m, 2H), 2.65-2.59 (m, 2H), 2.37-2.25 (m, 2H),1.82-1.74 (m, 4H), 1.30-1.20 (m, 1H). LC/MS: R_(t)=5.04 min, ES⁺ 450.2(FA long)

Example 68{(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-65) Step a:(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol

A suspension of(1R,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopent-2-en-1-ol(1.47 g, 0.00439 mol), sodium carbonate (1.1 g, 0.010 mol) and 10% Pd/C(0.3 g, 0.0003 mol) in EtOAc (20 mL, 0.2 mol) was stirred under anatmosphere of Hydrogen overnight. The reaction was purged with nitrogenand filtered through celite with EtOAc. The filtrate was concentrated toobtain 1.45 g (98%) of the title compound as a 5:1 mixture ofdiastereomers (desired:undesired).

Step b:(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]oxy}cyclopentylmethanesulfonate

The title compound was prepared following the procedure described inExample 35 step b.

Step c:(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)cyclopentylmethanesulfonate

A suspension of(1S,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopentylmethanesulfonate (690 mg, 0.0017 mol) and Palladium hydroxide, 20 wt. %Pd on carbon (160 mg, 0.00012 mol) in methanol (10 mL, 0.2 mol) wasstirred under an atmosphere of hydrogen for 2 hours. The reaction waspurged with nitrogen and filtered the mixture through celite with DCM.The filtrate was concentrated to obtain 350 mg (65%).

Step d:((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)methanol

To a solution of(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-cyclopentylmethanesulfonate (0.470 g, 0.00145 mol) in N,N-Dimethylformamide (6 mL,0.08 mol) was added sodium azide (0.4 g, 0.006 mol) 23° C., and themixture was heated at 55° C. for 3 hours. The reaction was cooled to 23°C., quenched by addition of water and extracted with Et₂O (3×), dried(Na₂SO₄), filtered and concentrated. The residue was purified by flashchromatography (10 to 25% ethyl acetate/hexane) to obtain 211 mg(53.7%).

Step e:((1S,2S,4R)-4-amino-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)methanol

A suspension of((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl)methanol(0.211 g, 0.000777 mol) and 10% Pd/C (0.047 g, 0.000044 mol) in EtOAc (6mL, 0.06 mol) was stirred under an atmosphere of Hydrogen overnight. Thereaction was purged with nitrogen and filtered the mixture throughcelite with DCM. The filtrate was concentrated to obtain 167 mg (87.5%)of the title compound.

Step f:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)amino]-cyclopentyl}methanol

A mixture of((1S,2S,4R)-4-amino-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)-methanol(0.132 g, 0.000538 mol), pyrimidine, 4,6-dichloro-(0.096 g, 0.00064 mol)and triethylamine (0.1 mL, 0.001 mol) in ethanol (1.5 mL, 0.025 mol) wassubjected to microwave irradiation (140° C.) for 60 minutes. Theresulting dark brown mixture was concentrated. The residue was purifiedby flash chromatography (0 to 10% MeOH/DCM) to give 158 mg (82%).

Step g:{(1S,2S,4R)-4-[(6-{[(1S)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-65)

The title compound was prepared following the procedure described inExample 44 (steps b and d) using (1S)-3,3-dimethylindan-1-amine. ¹H NMR(CD₃OD, 400 MHz) δ: 8.15 (s, 1H), 7.33-7.21 (m, 4H), 5.66 (s, 1H),4.39-4.36 (m, 1H), 4.31 (dd, I=7.3, 9.7 Hz, 1H), 4.13 (dd, J=7.4, 9.7Hz, 1H), 2.53-2.44 (m, 2H), 2.27-2.22 (m, 1H), 2.08-2.01 (m, 1H),1.91-1.84 (m, 2H), 1.78-1.72 (m, 1H), 1.41 (s, 3H), 1.27 (s, 3H) ppm.LC/MS: R_(t)=1.54 min, ES⁺ 448.38 (AA standard).

Example 69{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl]-amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate(Compound I-43)

The title compound was prepared following the procedure described inExample 34 using (1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-amine (Zhang,Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Zhang, Z. J. Org. Chem. 1999, 64,1774) in step b. ¹H NMR (400 MHz, CD₃OD) δ: 8.13 (s, 1H), 7.28-7.14 (m,4H), 5.88 (s, 1H), 5.56 (bs, 1H), 5.32 (bs, 1H), 4.40-4.30 (m, 2H),4.18-4.12 (m, 1H), 3.10-3.02 (m, 1H), 2.90-2.78 (m, 1H), 2.68-2.62 (m,1H), 2.57-2.47 (m, 1H), 2.31-2.23 (m, 1H), 2.11-1.91 (m, 3H), 0.91 (d,J=7.03 Hz, 3H) ppm. LC/MS: R_(t)=1.65 min, ES⁺ 435 (AA standard).

Example 70{(1S,2S,4R)-4-[(4-{[(1R)-2,2-Difluoro-2,3-dihydro-1H-inden-1-yl]amino}-1,3,5-triazin-2-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-147)

The title compound was prepared following the procedure in Example 46steps a-d using (1R)-5-chloro-2,2-difluoroindan-1-amine in step a. Thesulfamation was carried out according to the procedure in Example 65step d to give the title compound. ¹H NMR (CD₃OD 400 MHz) δ: 8.05 (d,0.5H), 7.95 (s, 0.5H), 7.30-7.28 (m, 4H), 6.06-5.89 (m, 1H), 4.62-4.59(m, 1H), 4.27-4.24 (m, 2H), 4.14-4.08 (m, 1H), 3.50-3.41 (m, 2H), 2.49(bs, 1H), 2.22-2.14 (m, 1H), 2.05-1.97 (m, 1H), 1.87-1.80 (m, 1H),1.76-1.70 (m, 1H) ppm. LC/MS: R_(t)=5.61 min, ES⁺ 457 (FA long).

Example 71{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compounds I-142 and I-143)

The title compound was prepared as a 1:1 mixture of diastereomersfollowing the procedures in Example 34.Rel-(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine, generated byadapting the following literature precedent: Marcune, B. F.; Karady, S.;Reider, P. J.; Miller, R. A.; Biba, M.; DiMichele, L.; Reamer, R. A. J.Org. Chem. 2003, 68, 8088-8091, was used as a coupling partner in stepb. The mixture was then separated by chiral HPLC (Chiralpak AD 20×250,eluent 85/15/0.1% hex/EtOH/DEA at 20 mL/min). Analytical data for{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-142): ¹H NMR (CD₃OD, 400 MHz) δ: 8.13 (d, J=0.8Hz, 1H), 7.20 (d, J=7.3 Hz, 1H), 7.15-7.01 (m, 3H), 5.93 (s, 1H), 5.48(bs, 1H), 5.34-5.31 (m, 1H), 4.40-4.37 (m, 1H), 4.32 (dd, J=7.6, 9.8 Hz,1H), 4.15 (dd, J=7.5, 9.6 Hz, 1H), 3.77-3.74 (m, 1H), 3.41 (s, 3H),3.00-2.92 (m, 1H), 2.78-2.71 (m, 1H), 2.55-2.48 (m, 1H), 2.31-2.19 (m,2H), 2.12-1.90 (m, 4H) ppm. LC/MS: R_(t)=6.22 min, ES⁺ 465 (FA long).Analytical data for{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)-oxy]cyclopentyl}methylsulfamate (Compound I-143): ¹H NMR (CD₃OD, 400 MHz) δ: 8.13 (d, J=0.8Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.15-7.08 (m, 3H), 5.93 (s, 1H), 5.50(bs, 1H), 5.34-5.31 (m, 1H), 4.40-4.37 (m, 1H), 4.32 (dd, J=7.2, 9.8 Hz,1H), 4.16 (dd, J=7.3, 9.8 Hz, 1H), 3.77-3.74 (m, 1H), 3.41 (s, 3H),3.00-2.92 (m, 1H), 2.78-2.71 (m, 1H), 2.55-2.49 (m, 1H), 2.31-2.19 (m,2H), 2.12-1.90 (m, 4H) ppm. LC/MS: R_(t)=6.09 min, ES⁺ 465 (FA long).

Example 72{(1R,2R,3S,4R)-4-[(6-{[(1R,2R)-2-(benzyloxy)cyclopentyl]amino}pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-85)

The title compound was prepared following the procedure described inExample 1, steps a-c using (1R,2R)-(+)-2-benzyloxycyclopentylamine andExample 65, step d. ¹H-NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.34-7.22(m, 5H), 5.59 (s, 1H), 4.58 (d, 1H, J=14.5 Hz), 4.55 (d, 1H, J=14.5 Hz),4.18 (dd, 1H, J=9.8, 4.8 Hz), 4.13 (dd, 1H, J=9.8, 5.5 Hz), 4.05-3.96(m, 1H), 3.95-3.84 (m, 3H), 3.76 (t, 1H, J=5.5 Hz), 2.41-2.25 (m, 2H),2.20-2.10 (m, 2H), 1.99-1.90 (m, 1H), 1.83-1.68 (m, 3H), 1.56-1.45 (m,1H), 1.29 (dt, 1H, J=12.5, 8.3 Hz). LC/MS: R_(t)=5.17 min, ES⁺ 473.2 (FAlong)

Example 73{(1R,2R,3S,4R)-4-[(6-{[(1S,2S)-2-(benzyloxy)cyclopentyl]amino}pyrimidin-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate (Compound I-92)

The title compound was prepared following the procedure described inExample 1, steps a-c using (1S,2S)-(+)-2-benzyloxycyclopentylamine andExample 65, step d. ¹H-NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.33-7.21(m, 5H), 5.57 (s, 1H), 4.57 (s, 2H), 4.19 (dd, 1H, J=9.6, 4.7 Hz), 4.14(dd, 1H, J=9.6, 5.5 Hz), 4.06-3.90 (m, 2H), 3.90-3.83 (m, 2H), 3.77 (t,1H, J=5.5 Hz), 2.45-2.28 (m, 2H), 2.20-2.10 (m, 2H), 2.00-1.88 (m, 1H),1.82-1.68 (m, 3H), 1.54-1.43 (m, 1H), 1.31 (dt, 1H, J=12.6, 8.4 Hz).LC/MS: R_(t)=1.16 min, ES⁺ 494.2 (FA standard).

Example 74((1R,2R,4S)-4-{[6-({(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylrel-sulfamate (Compound I-66) Step a: tert-butylrel-(2aR,7bR)-2-oxo-2,2a,3,7b-tetrahydro-1H-indeno[1,2-b]azete-1-carboxylate

To a mixed solution ofrel-(2aR,7bR)-1,2a,3,7b-tetrahydro-2H-indeno[1,2-b]azet-2-one (1.20 g,7.54 mmol) and N,N-dimethylaminopyridine (0.20 g, 2.00 mmol) inacetonitrile (24.0 mL) was added di-tert-butyldicarbonate (3.29 g, 15.1mmol) at 0° C. under an atmosphere of Argon, and the mixture was stirredfor 1 h at 23° C. The reaction mixture was added DCM (ca. 200 mL) andthen the organic layer was washed with saturated NaHCO₃ solution andbrine. After drying over MgSO₄, the suspension was filtered and thefiltrate was evaporated under vacuum. The residue was purified by flashchromatography (10 to 30% ethyl acetate/hexanes) to afford the titlecompound (1.85 g, 90%) as a light pink solid. ¹H-NMR (400 MHz, CDCl₃) δ:7.58 (d, 1H, J=7.5 Hz), 7.36-7.23 (m, 3H), 5.34 (d, 1H, J=5.0 Hz), 3.98(ddd, 1H, J=10.5, 5.0, 2.4 Hz), 3.38 (dd, 1H, J=17.4, 1.2 Hz), 3.13 (dd,1H, J=17.4, 10.5 Hz), 1.52 (s, 9H).

Step b: tert-butylrel-{(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}-carbamate

To tert-butylrel-(2aR,7bR)-2-oxo-2,2a,3,7b-tetrahydro-1H-indeno[1,2-b]azete-1-carboxylate(200 mg, 0.77 mmol) was added 2.00 M dimethylamine in THF (1.90 mL, 3.80mmol) in the sealed tube, and the mixture was microwaved at 120° C. for30 minutes. The reaction mixture was concentrated under vacuum, and thenthe residue was washed with small amount of hexane to give the titlecompound (226 mg, 91%) as a white solid.

Step c: rel-(1R,2R)-1-amino-N,N-dimethylindane-2-carboxamide

To a stirred solution of tert-butylrel-{(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}carbamate(690 mg, 2.15 mmol) in DCM (25.0 mL) was added zinc dibromide (970 mg,4.31 mmol) and ethanol (0.25 mL, 4.31 mmol), and the mixture was stirredfor 18 h. The reaction mixture was quenched by addition of water (20.0mL) and the resulting mixture was stirred for 2 h. To this mixture wasadded 1.00 M NaOH (30.0 mL) and extracted with DCM (3×100 mL). Theorganic layers were combined, dried over MgSO₄, filtered, and evaporatedunder vacuum. The residue was purified by flash chromatography (10 to30% Methanol/DCM) to afford the title compound (438 mg, 95%) as acolorless oil. LC/MS: R_(t)=0.89 min, ES⁺ 205.2 (AA standard).

Step d:((1R,2R,4S)-4-{[6-({(1R,2R)-2-[(dimethylamino)carbonyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylrel-sulfamate (Compound I-66)

The title compound was prepared following the procedure described inExample 34, steps a-c and Example 65, step d. ¹H-NMR (400 MHz, CD₃OD) δ:8.18 (s, 1H), 7.28-7.16 (m, 4H), 6.14-5.94 (bs, 1H), 5.81-5.71 (bs, 1H),5.31-5.23 (bs, 1H), 4.39-4.35 (m, 1H), 4.31 (dd, 1H, J=9.7, 7.5 Hz),4.13 (dd, 1H, J=9.7, 7.3 Hz), 3.98 (dd, 1H, J=15.6, 7.8 Hz), 3.53 (dd,1H, J=16.1, 7.3 Hz), 3.17 (s, 3H), 3.01 (dd, 1H, J=16.1, 8.1 Hz), 2.73(s, 3H), 2.56-2.44 (m, 1H), 2.29-2.20 (m, 1H), 2.04-1.88 (m, 3H). LC/MS:R_(t)=5.70 min, ES⁺ 492.2 (FA long).

Example 75((1R,2R,4S)-4-{[6-({(1R,2S)-2-[(dimethylamino)methyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylrel-sulfamate (Compound I-53) Step a:rel-(1R,2S)-2-[(dimethylamino)methyl]indan-1-amine

To a stirred suspension of lithium tetrahydroaluminate (256 mg, 6.74mmol) in THF (20.0 mL) was added a solution ofrel-(1R,2R)-1-amino-N,N-dimethylindane-2-carboxamide (580 mg, 2.70 mmol)in THF (10.0 mL) at 0° C. under an atmosphere of Argon, and then themixture was stirred for 1 h at 60° C. following by stirring for 14 h at23° C. The reaction mixture was quenched by addition of water and 1.00 MNaOH (5.00 mL), and the resulting mixture was stirred for 2 h. Thissuspension was filtered through a Celite pad, and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(5 to 20% Methanol/DCM with 1% NH₄OH) to afford the title compound (438mg, 95%) as a light brown oil.

Step b:((1R,2R,4S)-4-{[6-({(1R,2S)-2-[(dimethylamino)methyl]-2,3-dihydro-1H-inden-1-yl}amino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylrel-sulfamate (Compound I-53)

The title compound was prepared following the procedure described inExample 34, steps a-c usingrel-(1R,2S)-2-[(dimethylamino)methyl]indan-1-amine and Example 65, stepd. ¹H-NMR (400 MHz, CD₃OD) δ: 8.14 (s, 1H), 7.28-7.14 (m, 4H), 5.90-5.78(bs, 1H), 5.70-5.40 (bs, 1H), 5.38-5.28 (bs, 1H), 4.41-4.36 (m, 1H),4.32 (dd, 1H, J=9.8, 7.5 Hz), 4.15 (dd, 1H, J=9.8, 7.3 Hz), 3.09-3.00(m, 1H), 2.94-2.82 (m, 2H), 2.57-2.46 (m, 1H), 2.37 (br d, 2H, J=6.2Hz), 2.30-2.20 (m, 1H), 2.22 (s, 6H), 2.11-1.91 (m, 3H). LC/MS:R_(t)=4.34 min, ES⁺ 478.2 (FA long).

Example 76{(1S,2S,4R)-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-35) Step a: 1-(4-chlorophenyl)-3-methylbutan-2-ol

To a suspension of magnesium (2.98 g, 0.123 mol) in ether (30 mL) wasadded iodine (0.165 g, 0.000651 mol). To this was slowly added asolution of 4-chlorobenzyl bromide (24.00 g, 0.1168 mol) in ether (100mL). Upon addition of approximately 1 mL of solution an exotherm wasnoted and the mixture reached reflux. The addition of solution wasslowly continued to maintain a gentle reflux (˜90 min). On completion ofaddition, the reaction was heated for 30 minutes at 45° C. The reactionwas then cooled to 0° C. Isobutyraldehyde (12.7 mL, 0.140 mol) in ether(10 mL) was then added slowly over 2 hours. On completion of theaddition the reaction was allowed to warm to 23° C. and stirredovernight. The reaction was quenched with ice (˜200 g) and acidifiedwith 2M HCl (˜100 ml). This was extracted twice with ether and theorganic phase was evaporated. The residue was purified by flashchromatography (0 to 10% MeOH/CH₂Cl₂) to afford the title compound (9.89g, 43%).

Step b: 6-chloro-1,1-dimethylindane

To a solution of concentrated sulfuric acid (3.00 mL, 0.056 mol) inwater (0.28 mL, 0.0156 mol) was added1-(4-chlorophenyl)-3-methylbutan-2-ol (1.00 g, 0.00503 mol) over 30minutes. Additional sulfuric acid was added to dissolve the solid. Themixture was stirred for 2 hours. The mixture was poured onto ice thenextracted with ether. The organic phase was washed (water), dried(MgSO₄), filtered, and concentrated. The residue was filtered through aplug of silica with CH₂Cl₂ to afford the title compound (0.568 g, 63%).

Step c: 5-chloro-3,3-dimethylindan-1-one

To a solution of 6-chloro-1,1-dimethylindane (6.00 g, 0.0332 mol) inacetone (100 mL, 2 mol) was added 1.5 M of magnesium sulfate in water(30 mL) and potassium permanganate (12.3 g, 0.0780 mol). The reactionwas stirred overnight, the resulting deposit was filtered, and thesolution was concentrated to a reduced volume. The solution wasextracted with EtOAc (3×100 ml) and the organic layer was concentrated.Purification by flash chromatography (10% EtOAc/hexanes) afforded thetitle compound (4.33 g, 67%) as a white solid.

Step d:(2R)-2-[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]aminol-2-phenylethanol

To a mixture of 5-chloro-3,3-dimethylindan-1-one (4.33 g, 0.0222 mol)and (R)-(−)-2-phenylglycinol (3.2 g, 0.0234 mol) in toluene (200 mL) wasadded p-toluenesulfonic acid monohydrate (241 mg, 0.00127 mol). Thereaction was stirred at reflux (140° C.) under an atmosphere of nitrogenovernight, cooled and diluted with toluene. The mixture was washed withsaturated aqueous NaHCO₃ and water and the organic phase wasconcentrated. The residue was dissolved in THF (200 mL) under anatmosphere of nitrogen and cooled at 0° C. To this was added acetic acid(3.79 mL, 0.0667 mol) and sodium borohydride (1.26 g, 0.0334 mol). Thereaction was stirred under at atmosphere of nitrogen overnight. Thereaction was partitioned between CH₂Cl₂ and saturated aqueous NaHCO₃solution, separated, and the organic phase was evaporated. The residuewas purified by flash chromatography (20 to 100% EtOAc/hexanes) toafford the title compound (6.25 g, 90%) as a white solid.

Step e: (1S)-5-chloro-3,3-dimethylindan-1-amine HCl

To a solution of lead(IV) acetate (9.92 g, 0.0212 mol) in methanol (80mL) at 0° C. under an atmosphere of nitrogen was added(2R)-2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-phenylethanol(4.288 g, 0.01358 mol) as a solution in methanol (80 mL) dropwise over10 min. On completion of the addition, the mixture was warmed to 23° C.and stirred for 90 mins. To this was added 0.943 M of sodium carbonatein water (194 mL) and the mixture stirred for 10 min. CH₂Cl₂ (500 mL)was added and the mixture was filtered and washed with CH₂Cl₂. Thefiltrates were collected, the organic phase was separated and theaqueous extracted with CH₂Cl₂ (25 ml). The combined organics wereevaporated to dryness. The residue was dissolved in ethanol (500 mL) and10.4 M of hydrochloric acid in water (15.6 mL) was added. The mixturewas heated to reflux (95° C.) overnight. The mixture was cooled,evaporated and the residue was treated with ether and sonicated. Thesolid was isolated by filtration, washed with ether and dried to yieldthe title compound (2.704 g, 86%) as the HCl salt.

Step f:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-N-[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]pyridin-2-amine

To a mixture of[1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+)(3.4 mg, 0.0000052 mol) and potassium tert-butoxide (32.0 mg, 0.000286mol) under an atmosphere of argon was added4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine(0.1226 g, 0.0002596 mol) in 1.00 ml DME, followed by(1S)-5-chloro-3,3-dimethylindan-1-amine (0.048 g, 0.00025 mol) in 1 mlDME. The mixture was stirred overnight, and the solution was poured into50 ml EtOAc, washed with 10 ml water and concentrated. The residue waspurified by preparative plate chromatography (70% EtOAc/hexanes) toafford the title compound (28.0 mg, 18.0%).

Step g:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}methanol

The title compound was prepared by a method analogous to Example 34,step c.

Step h:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}methylsulfamate

To a solution of{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}-methanol(28.1 mg, 0.0000543 mol) in DMA (1.00 mL) was added chlorosulfonamide(0.0251 g, 0.000217 mol) in 0.50 ml acetonitrile. The mixture wasstirred for 30 min then poured into 50 ml EtOAc and 1.00 ml Et₃N. Thelayers were separated and the organic layer was washed (water) andconcentrated. The residue was purified by preparative platechromatography (85% EtOAc/hexanes) to afford the title compound (28.7mg, 89%) as a white solid.

Step i:{(1S,2S,4R)-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-pyridin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate

A solution of{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(2-{[(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)oxy]cyclopentyl}methylsulfamate (0.0287 g, 0.0000481 mol) in 3.0% (V/V) HCl in ethanol (25.0ml) was stirred for 4 hrs. The reaction was concentrated and dissolvedin 50 ml EtOAc and 1.00 ml triethylamine. The solution was washed withwater, concentrated, and the residue was isolated by preparative platechromatography (5% MeOH/EtOAc) to afford the title compound (16.5 mg,71%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ: 7.92 (d, 1H, J=5.8Hz), 7.22-7.20 (m, 1H), 7.17-7.14 (m, 2H), 6.16 (dd, 1H, J=6.0 Hz, J=2.3Hz) 5.85 (d, 1H, J=2.0 Hz), 5.30 (m, 1H), 4.92 (m, 1H), 4.70 (d, 1H,J=8.5 Hz), 4.50 (dt, 1H, J=5.0 Hz, J=1.9 Hz), 4.40 (dd, 1H, J=7.3 Hz,J=2.5 Hz), 4.28 (dd, 1H, J=7.3 Hz, J=2.5 Hz), 2.60 (bs, 1H), 2.50 (q,1H, J=7.0 Hz), 2.31-2.25 (m, 1H), 2.18-2.12 (m, 1H), 1.95-1.87 (m, 2H),1.79 (m, 1H), 1.25 (s, 6H). LC/MS: R_(t)=1.81 min, ES+ 482 (AAstandard).

Example 77((1S,2S,4R)-2-hydroxy-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}-cyclopentyl)methylsulfamate (Compound I-109) Step a: 2-amino-4-chloro-3-nitropyridine

To a solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) insulfuric acid (40.8 mL) with stirring at 0° C. was added a solution ofnitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol).The mixture was stirred (1 hr) then poured into 200 g ice and 100 mlwater. The solid was filtered and collected. The solution wasneutralized with 28% NH₃ in water to pH˜5. The solution was extractedwith EtOAc (3×300 ml). The solid also was dissolved in EtOAc andneutralized with 28% NH₃ in H₂O. The organic layers were combined,concentrated with 30 g silica gel, and purified by flash chromatography(20 to 60% EtOAc/hexanes) to afford the title compound (2.40 g, 36%) asa yellow solid.

Step b:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-3-nitropyridin-2-amine

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(0.782 g, 0.00217 mol) in THF (30.0 mL) was added NaH (0.156 g, 0.00650mol) and the mixture was stirred for 1 h. To this was added2-amino-4-chloro-3-nitropyridine (0.376 g, 0.00217 mol) and the mixturewas stirred overnight. The solution was concentrated and the residue waspurified by flash chromatography (25% EtOAc/hexanes) to afford the titlecompound (0.381 g, 35%) as a yellow solid.

Step c:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}pyridine-2,3-diamine

To a solution of4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-3-nitropyridin-2-amine(0.361 g, 0.000725 mol) in CH₂Cl₂ (6.00 mL) and acetic acid (3.00 mL)was added zinc (0.474 g, 0.00725 mol) and the mixture was stirred for 30min. The suspension was filtered and the filtrate was concentrated. Theresidue was dissolved in 50 ml EtOAc and 3 ml Et₃N then washed withwater (2×10 mL). The organic layer was dried (MgSO₄) and concentrated toafford the crude product (0.297 g, 88%).

Step d:7-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-2-(1-naphthyl)-3H-imidazo[4,5-b]pyridine

A mixture of 1-naphthalenecarboxaldehyde (115 mg, 0.000738 mol),4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}pyridine-2,3-diamine (115.1 mg, 0.0002460 mol) and sodiummetabisulfite (0.140 g, 0.000738 mol) in acetonitrile (2.00 mL) wassubject to microwave irradiation at 180° C. for 25 mins. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bypreparative plate chromatography (25% EtOAc/hexanes) to afford the titlecompound (0.101 g, 68%) as a white solid.

Step e:((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol

The title compound was prepared by a method analogous to Example 34,step c.

Step f:((1S,2S,4R)-2-hydroxy-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}-cyclopentyl)methylsulfamate (Compound I-109)

To a solution of((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol(0.0624 g, 0.000127 mol) in DMA (2.00 mL) was added chlorosulfonamide(0.0736 g, 0.000637 mol) and the mixture was stirred for 10 min. To thiswas added 12 M of hydrochloric acid in water (2.00 mL) dropwise at 0° C.and the mixture was stirred for 10 min. The mixture was added dropwiseto 50 mL of a 2N Na₂CO₃ solution, and was extracted by CH₂Cl₂ (3×30 ml).The combined organic layers were concentrated and the residue waspurified by flash chromatography (0 to 10% MeOH/EtOAc) to provide thetitle compound (14.5 mg, 25%) as a white solid. ¹H NMR (CD₃OD, 400 MHz)δ: 8.49 (m, 1H), 8.28 (m, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.97 (m, 1H),7.87 (dd, 1H, J=7.0 Hz, J=1.0 Hz), 7.63-7.54 (m, 3H), 6.89 (d, 1H, J=5.8Hz) 5.40 (bs, 1H), 4.45 (dt, 1H, J=4.9 Hz, J=1.9 Hz), 4.35 (dd, 1H,J=7.2 Hz, J=2.5 Hz), 4.19 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 2.62 (m, 1H),2.44-2.39 (m, 1H), 2.31-2.25 (m, 1H), 2.18-2.14 (m, 2H). LC/MS:R_(t)=1.55 min, ES+ 455 (AA standard).

Example 78((1S,2S,4R)-4-{[6-chloro-2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-56) Step a:N(4)-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]-5-chloro-3-nitropyridine-2,4-diamine

A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int.Application WO2004/016611),(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine(0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol(10.0 mL) was refluxed overnight. The reaction was concentrated andpurified by flash chromatography (30% EtOAc/hexanes) to afford the titlecompound (0.0768 g, 82%) as a yellow solid.

Step b:N(4)-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]-5-chloropyridine-2,3,4-triamine

N(4)-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]-5-chloro-3-nitropyridine-2,4-diamine(0.875 g, 0.00165 mol) and zinc (0.431 g, 0.00659 mol) was added toacetic acid (40.0 mL, 0.704 mol) with stirring for 10 mins. The mixturewas stirred for 10 min and the solid was filtered off. The filtrate wasconcentrated, dissolved in EtOAc (50 mL) washed with water (2×10). Tothe organic phase was added 2 ml Et₃N and the mixture was washed with 10mL water. The organic layer was concentrated and purified by flashchromatography (30% EtOAc/hexanes) to afford the title compound (0.746g, 90%) as a white solid.

Step c:((1S,2S,4R)-4-{[6-chloro-2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-56)

The title compound was prepared in an analogous fashion to Example 77,steps d-f. ¹H NMR (CD₃OD, 400 MHz) δ: 9.13 (d, 1H, J=9.9), 8.05-7.92 (m,4H), 7.65-7.57 (m, 3H), 5.82 (bs, 1H), 4.41 (dt, 1H, J=5.0 Hz, J=1.9Hz), 4.32 (dd, 1H, J=7.3 Hz, J=2.5 Hz), 4.17 (dd, 1H, J=7.3 Hz, J=2.5Hz), 3.25 (q, 2H, J=7.8 Hz), 2.40-2.28 (m, 2H), 2.05-1.94 (m, 2H).LC/MS: R_(t)=1.68 min, ES+ 488 (AA standard).

Example 79((1S,2S,4R)-4-{[6-(cyclopentylamino)pyrimidin-4-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-127)

The title compound was prepared in a manner analogous to Example 34,step b using cyclopentanamine and Example 76, steps g-i. ¹H NMR (CD₃OD,400 MHz) δ: 8.08 (s, 1H), 5.74 (s, 1H), 5.31 (bs, 1H), 4.38 (dt, 1H,J=5.0 Hz, J=1.9 Hz), 4.30 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 4.15 (dd, 1H,J=7.2 Hz, J=2.5 Hz), 2.51 (m, 1H), 2.34-2.26 (m, 1H), 2.09-1.96 (m, 6H),1.76 (m, 2H), 1.64 (m, 2H), 1.51 (m, 2H). LC/MS: R_(t)=1.46 min ES+ 373(AA standard).

Example 80 [(1S,2S,4R)-4-({2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyridin-4yl}oxy)-2-hydroxycyclopentyl]methyl sulfamate (CompoundI-94) Step a:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-2-chloropyridine

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(973.5 mg, 0.002699 mol) in DMF (8.00 mL, 0.103 mol) was added NaH (202mg, 0.00504 mol) (60% in oil). After stirring the mixture for 10minutes, 2-chloro-4-nitro-pyridine (400.0 mg, 0.00252 mol) was added andthe mixture was stirred overnight. The reaction was quenched with waterand extracted with (3×50 ml EtOAc). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain thetitle compound (0.9859 g, 83%) as a clear oil.

Step b:4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-N-[(1S)-2,3-dihydro-1H-inden-1-yl]pyridin-2-amine

To a mixture of[1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+)(7.8 mg, 0.000012 mol) and potassium tert-butoxide (73.7 mg, 0.000656mol) under an atmosphere of argon was added4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine(281.8 mg, 0.0005968 mol) in 1 ml DME. The solution was stirred for 5mins, then (S)-(+)-1-aminoindane (0.10 mL, 0.000776 mol) in 1.0 ml DMEwas added dropwise over 15 min. The solution was stirred overnight, thendissolved in 50 mL EtOAc, washed with water, and concentrated. Theresidue was purified by flash chromatography (30% EtOAc/hexanes) toafford the title compound (0.3219 g, 95%) as a white solid.

Step c: [(1S,2S,4R)-4-({2-[(1 S)-2,3-dihydro-1H-inden-1-ylamino]pyridin-4-yl}oxy)-2-hydroxycyclopentyl]methyl sulfamate (CompoundI-94)

The title compound was prepared in a manner analogous to Example 76,steps g-i. ¹H NMR (CDCl₃, 400 MHz) δ: 7.75 (d, 1H, J=6.0 Hz), 7.27-7.13(m, 3H), 6.16 (dd, 1H, J=6.3 Hz, J=2.4 Hz), 5.33 (t, 1H, J=7.5 Hz), 4.95(m, 1H), 4.50 (dt, 1H, J=5.1 Hz, J=2.0 Hz), 4.31 (dd, 1H, J=7.3 Hz,J=2.4 Hz), 4.15 (dd, 1H, J=7.3 Hz, J=2.4 Hz), 3.03-2.96 (m, 1H), 2.86(m, 1H), 2.61-2.46 (m, 2H), 2.29-2.23 (m, 1H), 2.10-2.03 (m, 1H),2.00-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.15-1.10 (m, 2H).

Example 81{(1S,2S,4R)-4-[(6-{[(1R,2S)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-149)

The title compound was prepared as a 1:1 mixture of with the compound inexample 82 according to Example 34, steps a-d, followed by HCl-mediateddesilylation.Rel-(1R,2S)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-amine, preparedaccording to the reference found in Example 71, was used as a couplingpartner in step b. The title compound was then isolated via chiral HPLC(Chiralcel OD 20×250, eluent 88/12/0.2% hex/EtOH/DEA at 20 mL/min). ¹HNMR (CD₃OD, 400 MHz) δ: 8.14 (d, J=0.7 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H),6.76-6.71 (m, 2H), 5.94 (s, 1H), 5.32 (bs, 1H), 4.39 (ddd, J=2.2, 5.2,5.2 Hz, 1H), 4.32 (dd, J=7.4, 9.8 Hz, 1H), 4.15 (dd, J=7.3, 9.8 Hz, 1H),3.73 (ddd, J=2.1, 3.8, 6.4 Hz, 1H), 3.67 (s, 3H), 3.40 (s, 3H),2.93-2.80 (m, 2H), 2.67 (ddd, J=5.6, 5.6, 11.6 Hz, 1H), 2.58-2.46 (m,1H), 2.28 (ddd, J=2.2, 6.8, 14.8 Hz, 1H), 2.25-2.16 (m, 1H), 2.12-1.87(m, 4H). LC/MS: R_(t)=1.25 min, ES⁺ 495 (FA standard).

Example 82{(1S,2S,4R)-4-[(6-{[(1S,2R)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-148)

The title compound was prepared as a 1:1 mixture of with the compound inexample 81 according to Example 34, steps a-d, followed by HCl-mediateddesilylation.Rel-(1R,2S)-2,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-amine, preparedaccording to the reference found in Example 71, was used as a couplingpartner in step b. The title compound was then isolated via chiral HPLC(Chiralcel OD 20×250, eluent 88/12/0.2% hex/EtOH/DEA at 20 mL/min). ¹HNMR (CD₃OD, 400 MHz) δ: 8.14 (d, J=0.7 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H),6.76-6.71 (m, 2H), 5.94 (s, 1H), 5.32 (bs, 1H), 4.39 (ddd, J=2.1, 5.1,5.1 Hz, 1H), 4.32 (dd, J=7.5, 9.8 Hz, 1H), 4.15 (dd, J=7.3, 9.8 Hz, 1H),3.74 (ddd, J=2.1, 3.9, 6.6 Hz, 1H), 3.67 (s, 3H), 3.40 (s, 3H),2.95-2.82 (m, 2H), 2.67 (ddd, J=5.7, 5.7, 11.5 Hz, 1H), 2.58-2.47 (m,1H), 2.28 (ddd, J=2.2, 6.8, 14.8 Hz, 1H), 2.25-2.16 (m, 1H), 2.12-1.87(m, 4H). LC/MS: R_(t)=1.25 min, ES⁺ 495 (FA standard).

Example 83{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1S,2R)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-151)

The title compound was prepared as a 1:1 mixture of with the compound inexample 84 according to example 34, steps a-d, followed by HCl-mediateddesilylation and then treatment with 1.0 equivalents of potassiumhydroxide as a solution in methanol to afford the correspondingpotassium salt.Rel-(1R,2S)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine,prepared according to the reference found in Example 71, was used as acoupling partner in step b. The title compound was then isolated viachiral HPLC (Chiralpak AD 20×250, eluent 85/15/0.1% hex/EtOH/DEA at 20mL/min). ¹H NMR (CD₃OD, 400 MHz) δ: 8.13 (s, 1H), 7.39-7.34 (m, 1H),7.25-7.18 (m, 2H), 7.13-7.06 (m, 1H), 5.90 (s, 1H), 5.64 (bs, 1H), 5.24(bs, 1H), 4.40 (ddd, J=1.7, 5.6, 5.6 Hz, 1H), 4.14 (ddd, J=1.3, 8.5,10.0 Hz, 1H), 4.00 (ddd, J=2.0, 6.4, 10.0 Hz, 1H), 3.78 (ddd, J=3.0,4.1, 10.4 Hz, 1H), 3.42 (s, 3H), 2.53-2.38 (m, 1H), 2.26 (dddd, J=1.8,1.8, 6.7, Hz, 1H), 2.12-1.81 (m, 4H), 1.77 (dd, J=2.0, 13.6 Hz, 1H),1.43 (s, 3H), 1.31 (s, 3H). LC/MS: R_(t)=1.61 min, ES⁺ 493 (FAstandard).

Example 84{(1S,2S,4R)-2-hydroxy-4-[(6-{[(1R,2S)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methylsulfamate (Compound I-150)

The title compound was prepared as a 1:1 mixture of with the compound inexample 83 according to example 34, steps a-d, followed by HCl-mediateddesilylation and then treatment with 1.0 equivalents of potassiumhydroxide as a solution in methanol to afford the correspondingpotassium salt.Rel-(1R,2S)-2-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-amine,prepared according to the reference found in Example 71, was used as acoupling partner in step b. The title compound was then isolated viachiral HPLC (Chiralpak AD 20×250, eluent 85/15/0.1% hex/EtOH/DEA at 20mL/min). ¹H NMR (CD₃OD, 400 MHz) δ: 8.14 (s, 1H), 7.40-7.35 (m, 1H),7.26-7.18 (m, 2H), 7.13-7.07 (m, 1H), 5.91 (s, 1H), 5.65 (bs, 1H), 5.25(bs, 1H), 4.40 (ddd, J=1.7, 5.6, 5.6 Hz, 1H), 4.14 (ddd, J=1.3, 8.5,10.0 Hz, 1H), 4.00 (ddd, J=1.8, 6.4, 9.9 Hz, 1H), 3.79 (ddd, J=3.4, 3.4,10.4 Hz, 1H), 3.42 (s, 3H), 2.52-2.38 (m, 1H), 2.32-2.21 (m, 1H),2.12-1.81 (m, 4H), 1.78 (dd, J=2.0, 13.5 Hz, 1H), 1.43 (s, 3H), 1.32 (s,3H). LC/MS: R_(t)=1.61 min, ES⁺ 493 (FA standard).

Example 85[(1S,2S,4S)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}-methyl)-2-hydroxycyclopentyl]methylsulfamate (1-33) Step a:2-Chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine

2,4-Dichloro-6-methylpyrimidine (2.54 g, 0.156 mol) was dissolved inethanol (100 mL) and N,N-Diisopropylethylamine (4.07 mL, 0.23 mol) wasadded followed by (S)-1-Aminoindan (2.00 mL, 0.156 mol). The solutionwas heated to reflux for 2 hours, TLC indicated complete conversion. Thesolvent was removed in vacuo and the residue was purified usingchromatography on silica gel using gradient 0 to 50% ethyl acetate inhexane to afford the title compound (1.95 g, 46%). LC/MS: R_(t)=1.90min, ES⁺ 260 (AA standard).

Step b: N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine

2-Chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine(1.95 g, 7.5 mmol) was dissolved in ethanol (5 mL) and 10% Pd/C (0.140g, 0.13 mmol) was added. The flask was filled with hydrogen and stirredovernight. At that time, TLC indicated complete conversion. Palladiumwas filtered off and the solvent was removed in vacuo. The residue waspurified using chromatography on silica gel using gradient 50 to 100%ethyl acetate in hexane to afford the title compound (1.65 g, 93%).LC/MS: R_(t)=1.51 min, ES⁺ 226 (AA standard).

Step c:(4aS,6S,7S,7aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-pyrimidin-4-yl}-methyl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol

N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine (0.575 g,2.55 mmol) was dissolved in THF (24 mL) and 1.8M Phenyllithium indi-n-butyl ether (2.98 mL, 5.36 mmol) was added and stirred for 1 hour.The mixture was cooled to 0° C. and a solution of(1aS,1bR,5aS,6aS)-3-(4-methoxyphenyl)hexahydrooxireno[4,5]cyclopenta[1,2-d][1,3]dioxine(0.634 g, 2.55 mmol) in THF (15 mL) was slowly added. The mixture wasstirred at 0° C. for 45 minutes and 23° C. for 2 hours. At that time,LCMS indicated ˜70% conversion. The reaction was quenched usingsaturated ammonium chloride (30 mL), extracted with ethyl acetate (3×20mL), dried with anhydrous magnesium sulfate, filtered, and evaporated invacuo. The residue was purified using chromatography on silica gel usinggradient 50 to 100% ethyl acetate in hexane to afford the title compound(0.465 g, 38%). LC/MS: R_(t)=1.77 min, ES⁺ 474 (AA standard).

Step d:O-[(4aS,6S,7S,7aR)-6-{[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-pyrimidin-4-yl}-methyl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenylthiocarbonate

(4aS,6S,7S,7aR)-6-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-pyrimidin-4-yl}-methyl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol(0.465 g, 0.98 mmol) was dissolved in DCM (17 mL) under an atmosphere ofargon and 4-(dimethylamino)-pyridine (0.24 g, 1.96 mmol) was addedfollowed by phenyl chlorothionocarbonate (0.204 mL, 1.47 mmol). Themixture was stirred for 1 hour. The solvent was concentrated in vacuoand the residue was purified via silica gel chromatography eluting witha gradient of 50 to 100% EtOAc in hexanes on a column pre-treated with1% TEA in hexanes to afford the title compound (0.508 g, 84%). LC/MS:R_(t)=2.38 min, ES⁺ 610 (AA standard).

Step e:N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-6-{[(4aS,6S,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]methyl}pyrimidin-4-amine

O-[(4aS,6S,7S,7aR)-6-{[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-pyrimidin-4-yl}methyl)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl]O-phenylthiocarbonate (0.508 g, 0.83 mmol) was dissolved in toluene (14 mL)under an atmosphere of nitrogen and tri-n-butyltin hydride (0.448 mL,1.67 mmol) was added followed by 2,2′-azo-bis-isobutyronitrile (0.027mg, 0.17 mmol). The solution was heated to reflux for 1 hour, themixture was cooled down, the solvent was concentrated to 30 mL and theresidue was purified via silica gel chromatography eluting with agradient of 50 to 100% EtOAc in hexanes to afford the title compound(0.280 g, 73%). LC/MS: R_(t)=1.94 min, ES⁺ 458 (AA standard).

Step f:(1S,2S,4S)-4-({6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}methyl)-2-(hydroxymethyl)cyclopentanol

N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-6-{[(4aS,6S,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]methyl}pyrimidin-4-amine(0.280 g, 0.61 mmol) was dissolved in THF (2 mL), water (2 mL) and AcOH(6 mL, 0.106 mmol) were added. The mixture was stirred under anatmosphere of argon for 60 h. The mixture was concentrated under reducedpressure and the residue was purified via silica gel chromatographyeluting with a gradient of 0 to 10% MeOH in DCM to afford the titlecompound (0.190 g, 91%). LC/MS: R_(t)=1.29 min, ES⁺ 340 (AA standard).

Step g:[(1S,2S,4S)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}methyl)-2-hydroxycyclopentyl]methylsulfamate (I-33)

The title compound was prepared following the procedure described inExample 65, step d. ¹H NMR (CD₃OD, 400 MHz, δ): 8.34 (s, 1H), 7.27-7.15(m, 4H), 6.41 (bs, 1H), 5.65-5.48 (m, 1H), 4.30-4.25 (m, 2H), 4.09 (dd,J=4.1, 4.1 Hz, 1H), 3.07-3.00 (m, 1H), 2.94-2.85 (m, 1H), 2.72-2.55 (m,4H), 2.43-2.35 (m, 1H), 1.93-1.85 (m, 2H), 1.75-1.67 (m, 1H), 1.58-1.51(m, 2H). LC/MS: R_(t)=1.38 min, ES⁺ 419 (AA standard).

Example 86((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-146) Step a: 2-(4,6-dichloropyrimidin-5-yl)ethanol

(4,6-dichloropyrimidin-5-yl)acetaldehyde (2.96 g, 15.5 mmol) wasdissolved in methanol (60 mL) and cooled at 0° C. Sodiumtetrahydroborate (0.879 g, 23.2 mmol) was added and the mixture wasstirred for 1 hour. TLC indicated complete conversion. The reaction wasquenched with water (20 mL), methanol was removed in vacuo and theresidue was extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried with magnesium sulfate, filtered and evaporated. Theresidue was purified using chromatography on silica gel using gradient 0to 100% ethyl acetate in methylene chloride to afford the title compound(1.90 g, 63%). LC/MS: R_(t)=0.93 min, ES⁺ 194 (AA standard).

Step b:2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethanol

2-(4,6-dichloropyrimidin-5-yl)ethanol (1.90 g, 9.84 mmol) was dissolvedin 1-butanol (97 mL) and N,N-Diisopropylethylamine (3.43 mL, 19.7 mmol)and (S)-1-Aminoindane (1.26 mL, 9.84 mmol) were added. The solution washeated at 130° C. for 3 days. Solvent was removed in vacuo and theresidue was purified using chromatography on silica gel using gradient 0to 100% ethyl acetate in methylene chloride to afford the title compound(2.80 g, 98%). LC/MS: R_(t)=1.63 min, ES⁺ 290 (AA standard).

Step c:2-(2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethyl)-1H-isoindole-1,3(2H)-dione

2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethanol(2.80 g, 9.66 mmol), phthalimide (1.56 g, 10.6 mmol) andtriphenylphosphine (2.79 g, 10.6 mmol) were dissolved in THF (105 mL)and the solution was cooled at 0° C. DIAD (2.09 mL, 10.6 mmol) was addeddropwise and the mixture was stirred 23° C. for 1 hour. The solvent wasremoved in vacuo and the residue was purified using chromatography onsilica gel using gradient 10 to 50% ethyl acetate in hexane to affordthe title compound (3.50 g, 86%). LC/MS: R_(t)=2.12 min, ES⁺ 419 (AAstandard).

Step d:5-(2-aminoethyl)-6-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine

2-(2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethyl)-1H-isoindole-1,3(2H)-dione(3.50 g, 8.32 mmol) was suspended in ethanol (102 mL) and hydrazinehydrate (1.62 mL, 33.3 mmol) was added. The mixture was heated to refluxfor 1 hour. At that time, LCMS indicated complete conversion. Themixture was cooled to 23° C., crystals were filtered off, the residuewas evaporated in vacuo and purified using chromatography on silica gelusing gradient 0 to 20% MeOH in methylene chloride to afford the titlecompound (1.20 g, 50%). LC/MS: R_(t)=1.29 min, ES⁺ 289 (AA standard).

Step e:N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine

5-(2-aminoethyl)-6-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine(1.00 g, 3.46 mmol) and N,N-diisopropylethylamine (1.21 mL, 6.92 mmol)were dissolved in 1,4-dioxane (19 mL) and the solution was heated in apressure tube at 160° C. for 48 hours. At that time, LCMS indicatedcomplete conversion. Solvent was removed in vacuo and the residue waspurified using chromatography on silica gel using gradient 0 to 20% MeOHin methylene chloride to afford the title compound (0.81 g, 93%). LC/MS:R_(t)=1.55 min, ES⁺ 253 (AA standard).

Step f:7-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-{[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentenyl-N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine

N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-amine(0.460 mg, 1.82 mmol) was dissolved in DMF (20 mL) and NaH (60%, 0.146g, 3.65 mmol) was added. The mixture was heated at 60° C. for 5 minutes.(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-{[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentenylmethanesulfonate (0.800 g, 1.82 mmol) in DMF (10 mL) was added and theresulting mixture was heated at 100° C. for 2 hours. The solution wascooled to 23° C., quenched with saturated brine (20 mL), extracted withethyl acetate (3×30 mL), dried with magnesium sulfate, filtered andevaporated in vacuo. The residue was purified using chromatography onsilica gel using gradient 0 to 30% ethyl acetate in hexane to afford thetitle compound (0.22 g, 20%). LC/MS: R_(t)=7.17 min, ES⁺ 596 (AANonpolar: Phenominex Luna 5 um C18 50×4.6 mm column at 2.5 ml/mingradient of ACN containing 50 to 0% 10 mM Ammonium Acetate in H₂O for 3min.)

Step g:((1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-5,6-dihydro-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methylsulfamate (Compound I-146)

The title compound was prepared following the procedures described inExample 34, step c and Example 65, step d. ¹H NMR (CD₃OD, 400 MHz) δ:7.93 (s, 1H), 7.23-7.12 (m, 4H), 5.64-5.60 (m, 1H), 4.87-4.83 (m, 1H),4.34-4.31 (m, 1H), 4.29 (dd, J=7.6, 9.6 Hz, 1H), 4.13 (dd, J=7.2, 9.6Hz, 1H), 3.58-3.53 (m, 2H), 3.03-2.95 (m, 1H), 2.90-2.77 (m, 3H),2.59-2.42 (m, 2H), 2.00-1.97 (m, 2H), 1.91-1.82 (m, 3H). LC/MS:R_(t)=4.98 min, ES⁺ 446 (FA long).

Example 87((1R,2R,3S,4R)-4-{[2-2,3-dihydro-H-indol-1-ylcarbonyl)pyridine-4-yl}amino}-2,3-dihydroxycyclopentyl)methylsulfamate(Compound I-145)

¹H NMR (400 MHz, CD₃OD) δ: 8.20-8.00 (m, 2H), 7.30-6.70 (m, 5H),4.26-4.02 (m, 3H), 3.88-3.78 (m, 2H), 3.17-3.11 (m, 2H) 2.50-2.30 (m,2H), 1.40-1.20 (m, 3H), ppm. LC/MS: R_(t)=0.95 min, ES⁺ 449 (AAstandard).

Example 88{(1R,2R,3S,4R)-4-[(2-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}pyridine-4-yl)amino]-2,3-dihydroxycyclopentyl}methylsulfamate(Compound I-144)

¹H NMR (CD₃OD, 300 MHz) δ: 8.05 (d, J=7.5 Hz, 1H), 7.50 (bs, 1H),7.32-7.16 (m, 4H), 6.97-6.92 (m, 1H), 5.64 (t, J=7.54 Hz, 1H), 4.17 (d,J=5.09 Hz, 2H), 4.09-3.80 (m, 3H), 3.15-3.04 (m, 1H), 3.00-2.87 (m, 1H),2.66-2.54 (m, 1H), 2.45-2.29 (m, 2H), 2.11-1.97 (m, 1H), 1.44-1.34 (m,1H) ppm. LC/MS: R_(t)=1.35 min, ES⁺ 463 (AA standard).

Example 89((1S,2S,4R)-4-{[8-(3-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-60) Step a: 6-chloro-4,5-diaminopyrimidine

A suspension of 5-Amino-4,6-dichloropyrimidine (3 g, 0.02 mol) inammonia (25 mL, 7N/MeOH, 0.175 mole) was heated at 118° C. overnight(under pressure). The reaction was cooled to 23° C., filtered and washedwith ethanol to obtain 1.92 g (70%).

Step b: 6-chloro-8-(3-chlorophenyl)-9H-purine

To a mixture of 6-Chloro-4,5-diaminopyrimidine (0.70 g, 4.84 mmol) and3-chlorobenzoic acid (0.76 g, 4.84 mmol) in the flask was addedphosphoryl chloride (40.0 mL), and the resulting mixture was stirred for16 h at 100° C. The reaction mixture was evaporated to remove excessphosphoryl chloride, and the residue was added to water (20 mL). Theprecipitate was filtered and purified by flash chromatography (0 to 5%Methanol/DCM) to afford the title compound (1.28 g, 31%) as a yellowsolid. LC/MS: R_(t)=1.59 min, ES⁺ 265.0 (FA standard).

Step c:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-8-(3-chlorophenyl)-9H-purin-6-amine

A solution of 6-chloro-8-(3-chlorophenyl)-9H-purine (155 mg, 0.58 mmol),(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine(200 mg, 0.56 mmol) (Example 128, steps a-c), andN,N-diisopropylethylamine (0.20 mL, 1.17 mmol) in ethanol (2.00 mL) wasmicrowaved at 160° C. for 30 minutes. The reaction mixture wasconcentrated under vacuum, and the residue was purified by flashchromatography (0 to 5% Methanol/DCM) to afford the title compound (275mg, 76%) as a light yellow solid.

Step d:((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[8-(3-chlorophenyl)-9H-purin-6-yl]amino}cyclopentyl)methanol

The title compound was prepared following the procedure described inExample 34, step c. LC/MS: R_(t)=2.07 min, ES⁺ 474.2 (AA standard).

Step e:((1S,2S,4R)-4-{[8-(3-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)-methylsulfamate (Compound I-60)

The title compound was prepared following the procedure described inExample 65, step d. ¹H-NMR (400 MHz, CD₃OD) δ: 8.22 (s, 1H), 8.09 (s,1H), 8.00-7.94 (m, 1H), 7.54-7.48 (m, 2H), 4.93-4.84 (m, 1H), 4.44-4.40(m, 1H), 4.35 (dd, 1H, J=9.7, 7.8 Hz), 4.17 (dd, 1H, J=9.7, 7.3 Hz),2.64-2.54 (m, 1H), 2.35 (ddd, 1H, J=14.0, 7.6, 1.2 Hz), 2.20-2.10 (m,1H), 1.96 (ddd, 1H, J=14.0, 7.0, 4.8 Hz), 1.86 (ddd, 1H, J=13.0, 8.2,3.8 Hz). LC/MS: R_(t)=5.48 min, ES⁺ 439.1 (FA long)

Example 90((1S,2S,4R)-4-{[8-(2,6-dimethoxyphenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-93)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2,6-dimethoxybenzoic acid. ¹H-NMR (400 MHz,CD₃OD) δ: 8.21 (s, 1H), 7.46 (t, 1H, J=8.6 Hz), 6.78 (d, 2H, J=8.6 Hz),4.90-4.79 (m, 1H), 4.43-4.38 (m, 1H), 4.34 (dd, 1H, J=9.6, 7.5 Hz), 4.17(dd, 1H, J=9.6, 7.3 Hz), 3.81 (s, 6H), 2.62-2.52 (m, 1H), 2.34 (ddd, 1H,J=14.0, 7.5, 1.7 Hz), 2.15 (ddd, 1H, J=13.8, 10.3, 8.9), 1.93 (ddd, 1H,J=14.0, 6.5, 5.3 Hz), 1.84 (ddd, 1H, J=13.8, 8.6, 3.8 Hz). LC/MS:R_(t)=4.30 min, ES⁺ 465.2 (FA long).

Example 91[(1S,2S,4R)-2-hydroxy-4-({8-[2-(trifluoromethyl)phenyl]-9H-purin-6-yl}-amino)cyclopentyl]methylsulfamate (Compound I-122)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using α,α,α-Trifluoro-o-toluic acid. ¹H-NMR (400MHz, CD₃OD) δ: 8.26 (s, 1H), 7.92 (dd, 1H, J=7.0, 1.9 Hz), 7.82-7.71 (m,3H), 4.96-4.85 (m, 1H), 4.43-4.38 (m, 1H), 4.34 (dd, 1H, J=9.8, 7.4 Hz),4.16 (dd, 1H, J=9.8, 7.3 Hz), 2.63-2.52 (m, 1H), 2.34 (ddd, 1H, J=14.0,7.5, 1.8 Hz), 2.15 (ddd, 1H, J=13.5, 10.6, 8.8 Hz), 1.95 (ddd, 1H,J=14.0, 7.1, 5.0 Hz), 1.85 (ddd, 1H, J=13.5, 8.6, 3.8 Hz). LC/MS:R_(t)=5.17 min, ES⁺ 473.2 (FA long).

Example 92((1S,2S,4R)-2-hydroxy-4-{[8-(2-phenoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-37)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2-phenoxybenzoic acid. ¹H-NMR (400 MHz,THF-d8) δ: 8.40 (br d, 1H, J=7.5 Hz), 8.18 (bs, 1H), 7.43-7.34 (m, 3H),7.25-7.13 (m, 4H), 6.94 (d, 1H, J=8.3 Hz), 6.87 (br d, 1H, J=7.5 Hz),5.17-4.93 (m, 1H), 4.41-4.35 (m, 1H), 4.35 (dd, 1H, J=9.8, 7.7 Hz), 4.13(dd, 1H, J=9.8, 7.3 Hz), 2.63-2.52 (m, 1H), 2.35-2.25 (m, 1H), 2.20-2.06(m, 1H), 2.01-1.91 (m, 1H), 1.87 (ddd, 1H, J=13.3, 8.8, 4.4 Hz). LC/MS:R_(t)=5.83 min, ES⁺ 497.2 (FA long).

Example 93((1S,2S,4R)-2-hydroxy-4-{[8-(1-naphthyl)-9H-purin-6-yl]amino}cyclopentyl)-methylsulfamate (Compound I-49)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 1-naphthalenecarboxylic acid. ¹H-NMR (400MHz, CD₃OD) δ: 8.70-8.55 (bs, 1H), 8.26 (s, 1H), 8.02 (d, 1H, J=8.3 Hz),7.98-7.93 (m, 1H), 7.84 (dd, 1H, J=7.1, 1.1 Hz), 7.61-7.52 (m, 3H),5.01-4.80 (m, 1H), 4.41-4.37 (m, 1H), 4.34 (dd, 1H, J=9.5, 7.6 Hz), 4.16(dd, 1H, J=9.5, 7.3 Hz), 2.61-2.50 (m, 1H), 2.34 (ddd, 1H, J=14.0, 7.6,1.5 Hz), 2.20-2.10 (m, 1H), 1.94 (ddd, 1H, J=14.0, 7.0, 4.9 Hz), 1.84(ddd, 1H, J=13.1, 8.3, 3.8 Hz). LC/MS: R_(t)=5.48 min, ES⁺ 455.1 (FAlong).

Example 94{(1S,2S,4R)-4-[(8-dibenzo[b,d]furan-4-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-39)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using dibenzofuran-4-carboxylic acid. ¹H-NMR (400MHz, CD₃OD) δ: 8.25 (s, 1H), 8.15-8.07 (m, 2H), 8.04 (d, 1H, J=7.9 Hz),7.74 (d, 1H, J=8.2 Hz), 7.56-7.50 (m, 1H), 7.46 (t, 1H, J=7.6 Hz), 7.40(dd, 1H, J=7.9, 7.2 Hz), 4.91-4.77 (m, 1H), 4.47-4.43 (m, 1H), 4.38 (dd,1H, J=9.8, 7.5 Hz), 4.20 (dd, 1H, J=9.8, 7.2 Hz), 2.67-2.56 (m, 1H),2.38 (ddd, 1H, J=14.0, 7.8, 1.2 Hz), 2.24-2.13 (m, 1H), 1.99 (ddd, 1H,J=14.0, 6.7, 5.0 Hz), 1.89 (ddd, 1H, J=13.0, 8.4, 3.7 Hz). LC/MS:R_(t)=5.74 min, ES⁺ 495.0 (FA long).

Example 95{(1S,2S,4R)-4-[(8-Biphenyl-3-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methylsulfamate (Compound I-105)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using biphenyl-3-carboxylic acid. ¹H-NMR (400MHz, THF-d8) δ: 12.38-12.25 (bs, 1H), 10.95-10.80 (bs, 1H), 8.38 (t, 1H,J=1.8 Hz), 8.17 (s, 1H), 8.05 (d, 1H, J=7.3 Hz), 7.72-7.68 (m, 3H), 7.55(t, 1H, J=7.6 Hz), 7.48-7.43 (m, 2H), 7.35 (tt, 1H, J=7.3, 1.3 Hz), 6.87(br d, 1H, J=6.5 Hz), 6.57-6.45 (bs, 2H), 5.15-4.90 (m, 1H), 4.37-4.31(m, 1H), 4.31 (dd, 1H, J=9.5, 7.8 Hz), 4.09 (dd, 1H, J=9.5, 7.3 Hz),3.95-3.85 (bs, 1H), 2.31-2.21 (m, 1H), 2.16-2.04 (m, 1H), 1.94 (ddd, 1H,J=13.1, 8.0, 4.4 Hz), 1.84 (ddd, 1H, J=13.3, 8.8, 4.2 Hz). LC/MS:R_(t)=6.17 min, ES⁺ 481.0 (FA long).

Example 96((1S,2S,4R)-2-hydroxy-4-{[8-(5,6,7,8-tetrahydronaphthalen-1-yl)-9H-purin-6-yl]amino}cyclopentyl)methylsulfamate (Compound I-126)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 5,6,7,8-tetrahydro-naphthalene-1-carboxylicacid. ¹H-NMR (400 MHz, CD₃OD) δ: 8.22 (s, 1H), 7.38-7.32 (m, 1H),7.25-7.19 (m, 2H), 4.92-4.82 (m, 1H), 4.42-4.38 (m, 1H), 4.34 (dd, 1H,J=9.5, 7.8 Hz), 4.16 (dd, 1H, J=9.5, 7.3 Hz), 2.93-2.83 (m, 4H),2.62-2.51 (m, 1H), 2.33 (ddd, 1H, J=13.8, 7.5, 1.8 Hz), 2.15 (ddd, 1H,J=13.5, 10.3, 8.8 Hz), 1.94 (ddd, 1H, J=13.8, 7.1, 4.8 Hz), 1.88-1.73(m, 5H). LC/MS: R_(t)=5.22 min, ES⁺ 459.1 (FA long).

Example 97((1S,2S,4R)-2-hydroxy-4-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methylsulfamate (Compound I-87)

The title compound was prepared following the procedures described inExample 33 (steps a-b, e-f) and Example 65 (step d) using(1R,3S,4S)-3-{[tert-butyl(dimethyl)-silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol.¹H-NMR (400 MHz, CD₃OD) δ: 8.53-8.46 (m, 1H), 8.52 (s, 1H), 8.08 (d, 1H,J=8.0 Hz), 8.01-7.96 (m, 1H), 7.88 (dd, 1H, J=7.3, 1.2 Hz), 7.65-7.55(m, 3H), 5.98-5.91 (m, 1H), 4.90-4.85 (m, 1H), 4.48-4.43 (m, 1H), 4.36(dd, 1H, J=9.8, 7.5 Hz), 4.20 (dd, 1H, J=9.8, 7.2 Hz), 2.71-2.60 (m,1H), 2.44 (ddd, 1H, J=15.0, 6.7, 1.9 Hz), 2.27 (ddd, 1H, J=15.0, 5.0,4.5 Hz), 2.20-2.13 (m, 1H). LC/MS: R_(t)=6.48 min, ES⁺ 456.0 (FA long).

Example 98{(1S,2S,4R)-4-[(8-biphenyl-2-yl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methylsulfamate (Compound I-48)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2-biphenylcarboxylic acid. ¹H-NMR (400 MHz,CD₃OD) δ: 8.14 (s, 1H), 7.73 (dd, 1H, J=7.6, 1.1 Hz), 7.65-7.60 (m, 1H),7.57-7.50 (m, 2H), 7.30-7.24 (m, 3H), 7.22-7.18 (m, 2H), 4.88-4.77 (m,1H), 4.41-4.36 (m, 1H), 4.33 (dd, 1H, J=9.7, 7.5 Hz), 4.15 (dd, 1H,J=9.7, 7.5 Hz), 2.60-2.48 (m, 1H), 2.34-2.25 (m, 1H), 2.16-2.04 (m, 1H),1.94-1.85 (m, 1H), 1.84-1.74 (m, 1H). LC/MS: R_(t)=5.43 min, ES⁺ 481.0(FA long).

Example 99((1S,2S,4R)-4-{[8-(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-100)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid. ¹H-NMR (400MHz, CD₃OD) δ: 8.30-8.19 (m, 1H), 8.06-8.02 and 7.90-7.80 (each bs,total 1H), 7.34-7.28 (m, 1H), 6.99 (t, 1H, J=6.5 Hz), 4.90-4.80 (m, 1H),4.45-4.40 (m, 1H), 4.35 (dd, 1H, J=9.7, 7.7 Hz), 4.18 (dd, 1H, J=9.7,7.5 Hz), 3.15 (bs, 2H), 2.64-2.52 (m, 1H), 2.44-2.30 (m, 1H), 2.23-2.10(m, 1H), 2.01-1.90 (m, 1H), 1.86 (ddd, 1H, J=13.0, 8.2, 3.7 Hz), 1.64(bs, 3H), 1.61 (s, 3H). LC/MS: R_(t)=5.17 min, ES⁺ 475.3 (FA long).

Example 100[(1S,2S,4R)-4-({8-[4-(dimethylamino)-1-naphthyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-64)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 4-dimethylaminonaphthalene-1-carboxylicacid. ¹H-NMR (400 MHz, CD₃OD) δ: 8.70-8.58 (bs, 1H), 8.34-8.28 (m, 1H),8.25 (s, 1H), 7.77 (d, 1H, J=7.9 Hz), 7.60-7.53 (m, 1H), 7.21 (d, 1H,J=7.9 Hz), 4.98-4.84 (m, 1H), 4.44-4.39 (m, 1H), 4.35 (dd, 1H, J=9.8,7.6 Hz), 4.17 (dd, 1H, J=9.8, 7.3 Hz), 2.64-2.53 (m, 1H), 2.35 (ddd, 1H,J=14.0, 7.6, 1.6 Hz), 2.22-2.12 (m, 1H), 1.97 (ddd, 1H, J=14.0, 7.0, 5.0Hz), 1.87 (ddd, 1H, J=12.5, 8.6, 3.5 Hz). LC/MS: R_(t)=5.39 min, ES⁺498.0 (FA long).

Example 101((1S,2S,4R)-2-hydroxy-4-{[8-(3-methoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-99)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 3-Methoxybenzoic acid. ¹H-NMR (400 MHz,MeOD, δ): 8.22 (s, 1H), 7.62 (m, 2H), 7.43 (t, J=7.9 Hz, 1H), 7.07 (dd,J=2.3 Hz, 8.3 Hz, 1H), 4.42 (t, J=4.3 Hz, 1H), 4.35 (dd, J=7.7 Hz, 9.7Hz, 1H), 4.17 (dd, J=7.3 Hz, 9.7 Hz, 1H), 3.89 (s, 1H), 2.59 (m, 1H),2.35 (ddd, J=1.1 Hz, 7.6 Hz, 14.2 Hz, 1H), 2.16 (td, 1H, J=9.4 Hz, 13.3Hz), 1.96 (ddd, J=5.1 Hz, J=6.9 Hz, J=14.0 Hz, 1H), 1.86 (ddd, J=3.8 Hz,8.5 Hz, 13.1 Hz, 1H). LC/MS: R_(t)=1.33 min, ES⁺ 435 (AA standard).

Example 102{(1S,2S,4R)-4-[(8-benzyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}methylsulfamate (Compound I-88)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using Benzeneacetic acid. ¹H-NMR (400 MHz, CD₃OD)δ: 8.17 (s, 1H), 7.35-7.21 (m, 5H), 4.84-4.71 (m, 1H), 4.40-4.35 (m,1H), 4.33 (dd, J=7.5, 9.8 Hz, 1H), 4.19 (s, 2H), 4.14 (dd, J=7.3, 9.8Hz, 1H), 2.59-2.45 (m, 1H), 2.34-2.23 (m, 1H), 2.17-2.04 (m, 1H),1.92-1.82 (m, 1H), 1.82-1.72 (m, 1H) ppm. LC/MS: R_(t)=3.94 min, ES⁺ 419(FA Waters).

Example 103((1S,2S,4R)-2-hydroxy-4-{[8-(1,2,3,4-tetrahydronaphthalen-1-yl)-9H-purin-6-yl]amino}cyclopentyl)methylsulfamate (Compound I-121)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 1,2,3,4-Tetrahydro-1-naphthalenylhydroperoxide. ¹H NMR (400 MHz, CD₃OD) δ: 8.17 (s, 1H), 7.26-7.03 (m,3H), 6.93-6.83 (m, 1H), 4.82-4.70 (m, 1H), 4.47-4.28 (m, 3H), 4.17-4.10(m, 1H), 3.00-2.79 (m, 2H), 2.57-2.43 (m, 1H), 2.33-2.04 (m, 4H),1.98-1.68 (m, 5H) ppm. LC/MS: R_(t)=4.30 min, ES⁺ 459 (FA Waters).

Example 104[(1S,2S,4R)-4-({8-[2-(dimethylamino)phenyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-137)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2-Dimethylaminobenzoic acid. ¹H NMR (400MHz, CD₃OD) δ: 8.23 (s, 1H), 8.06-7.93 (m, 1H), 7.48-7.39 (m, 1H),7.35-7.28 (m, 1H), 7.20-7.12 (m, 1H), 4.45-4.39 (m, 1H), 4.36 (dd,J=7.8, 9.8 Hz, 1H), 4.18 (dd, J=7.3, 9.5 Hz, 1H), 2.68 (s, 6H),2.63-2.52 (m, 1H), 2.40-2.29 (m, 1H), 2.21-2.09 (m, 1H), 1.99-1.90 (m,1H), 1.89-1.80 (m, 1H) ppm. LC/MS: R_(t)=3.28 min, ES⁺ 448 (FA Waters).

Example 105((1S,2S,4R)-4-{[8-(2,3-dihydro-1,4-benzodioxin-5-yl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-41)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2,3-Dihydro-1,4-benzodioxine-5-carboxylicacid. ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.30-7.79 (m, 2H), 7.69-7.61 (m, 1H),7.06-6.89 (m, 3H), 4.94-4.15 (m, 9H), 2.46-2.40 (m, 1H), 2.26-1.84 (m,4H), 1.82-1.67 (m, 2H) ppm. LC/MS: R_(t)=3.93 min, ES⁺ 463 (FA Waters).

Example 106[(1S,2S,4R)-4-({8-[2-(benzyloxy)phenyl]-9H-purin-6-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-68)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using 2-Benzyloxybenzoic acid. ¹H NMR (400 MHz,CD₃OD) δ: 8.38-8.02 (m, 2H), 7.49-7.07 (m, 8H), 5.63-5.29 (m, 2H),4.44-4.39 (m, 1H), 4.35 (dd, J=7.8, 9.8 Hz, 1H), 4.17 (dd, J=7.3, 9.8Hz, 11H), 2.65-2.48 (m, 1H), 2.41-2.28 (m, 1H), 2.22-2.10 (m, 1H),2.02-1.78 (m, 2H) ppm. LC/MS: R_(t)=4.71 min, ES⁺ 511 (FA Waters).

Example 107{(1S,2S,4R)-4-[(8-cyclohexyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methylsulfamate (Compound I-128)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using Cyclohexanecarboxylic acid. ¹H NMR (CD₃OD,400 MHz) δ: 8.16 (s, 1H), 4.82-4.77 (m, 1H), 4.42-4.39 (m, 1H), 4.34(dd, J=7.6, 9.7 Hz, 1H), 4.16 (dd, J=7.3, 9.7 Hz, 1H), 2.89-2.83 (m,1H), 2.59-2.52 (m, 1H), 2.35-2.29 (m, 1H), 2.17-2.07 (m, 3H), 1.95-1.75(m, 5H), 1.67-1.27 (m, 5H) ppm. LC/MS: R_(t)=1.30 min, ES⁺ 411.08 (AAstandard).

Example 108{(1S,2S,4R)-4-[(8-tert-butyl-9H-purin-6-yl)amino]-2-hydroxycyclopentyl}-methylsulfamate (Compound I-131)

The title compound was prepared following the procedure described inExample 89 (steps a-e) using Trimethylacetic acid. ¹H NMR (CD₃OD, 400MHz) δ: 8.17 (s, 1H), 4.83-4.76 (m, 1H), 4.42-4.39 (m, 1H), 4.34 (dd,J=7.5, 9.5 Hz, 1H), 4.16 (dd, J=7.3, 9.8 Hz, 1H), 2.59-2.53 (m, 1H),2.35-2.30 (m, 1H), 2.17-2.09 (m, 1H), 1.95-1.88 (m, 1H), 1.85-1.78 (m,1H), 1.44 (s, 9H) ppm. LC/MS: R_(t)=1.08 min, ES⁺ 385.24 (AA standard).

Example 109((1S,2S,4R)-4-{[8-(4-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-111) Step a: 6-chloro-8-(4-chlorophenyl)-9H-purine

To a solution of 6-Chloro-4,5-diaminopyrimidine (1 g, 0.007 mol)(Example 89, step a) in 1,4-Dioxane (60 mL, 0.8 mol) was added4-Chlorobenzaldehyde (2.2 g, 0.016 mol) and Ferric chloride (2.5 g,0.015 mol) mixed with 28.6 g silica gel, and the mixture was heated at100° C. for 20 hours. The reaction was cooled to 23° C., filtered andwashed with 10% ethanol/ethyl acetate and concentrated. The residue wasdissolved in ethyl acetate and washed with water, brine, andconcentrated. The residue was triturated in diethyl ether to obtain 272mg (10%). LC/MS: R_(t)=1.54 min, ES⁺ 265 (AA standard).

Step b:((1S,2S,4R)-4-{[8-(4-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)-methylsulfamate (Compound I-111)

The title compound was prepared following the procedure described inExample 89 (steps c-d) and Example 1, step d. ¹H NMR (CD₃OD, 400 MHz) δ:8.22 (s, 1H), 8.03 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 4.90-4.85(m, 1H), 4.43-4.41 (m, 1H), 4.35 (dd, J=7.6, 9.7 Hz, 1H), 4.17 (dd,J=7.3, 9.7 Hz, 1H), 2.62-2.56 (m, 1H), 2.37-2.31 (m, 1H), 2.20-2.12 (m,1H), 2.00-1.93 (m, 1H), 1.89-1.82 (m, 1H) ppm. LC/MS: R_(t)=1.35 min,ES⁺ 439.29 (AA standard).

Example 110{(1S,2S,4R)-2-hydroxy-4-[(8-phenyl-9H-purin-6-yl)amino]cyclopentyl}methylsulfamate (Compound I-69)

The title compound was prepared following the procedures described inExample 109 (step a) using benzaldehyde and Example 1 (step d) followedby TBAF deprotection of the TBS group. ¹H NMR (CD₃OD, 400 MHz) δ: 8.22(s, 1H), 8.06-8.04 (m, 2H), 7.56-7.51 (m, 3H), 4.90-4.84 (m, 1H),4.43-4.41 (m, 1H), 4.38-4.33 (m, 1H), 4.20-4.15 (m, 1H), 2.62-2.56 (m,1H), 2.37-2.31 (m, 1H), 2.20-2.11 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.81(m, 1H) ppm. LC/MS: R_(t)=1.24 min, ES⁺ 405 (AA standard).

Example 111[(1S,2S,4R)-2-hydroxy-4-({8-[2-(trifluoromethoxy)phenyl]-9H-purin-6-yl}-amino)cyclopentyl]methylsulfamate (Compound I-62)

The title compound was prepared following the procedures described inExample 109 (step a) and Example 89 (steps c-e) using2-(Trifluoromethoxy)benzaldehyde. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (bs,1H), 8.05-7.95 (m, 1H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 4.45-4.39(m, 1H), 4.35 (dd, J=7.5, 9.8 Hz, 1H), 4.17 (dd, J=7.3, 9.5 Hz, 1H),2.67-2.51 (m, 1H), 2.40-2.29 (m, 1H), 2.22-2.10 (m, 1H), 2.07-1.91 (m,1H), 1.90-1.81 (m, 1H) ppm. LC/MS: R_(t)=5.71 min, ES⁺ 489 (AA Waters).

Example 112((1S,2S,4R)-2-hydroxy-4-{[8-(2-methoxyphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-133)

The title compound was prepared following the procedure described inExample 111 using 2-Methoxybenzaldehyde. ¹H NMR (400 MHz, CD₃OD) δ:8.41-8.00 (m, 2H), 7.53-7.44 (m, 1H), 7.24-7.16 (m, 1H), 7.15-7.06 (m,1H), 4.85-4.76 (m, 1H), 4.45-4.40 (m, 1H), 4.36 (dd, J=7.8, 9.8 Hz, 1H),4.18 (dd, J=7.3, 9.5 Hz, 1H), 4.05 (bs, 3H), 2.64-2.51 (m, 1H),2.41-2.30 (m, 1H), 2.22-2.10 (m, 1H), 2.00-1.79 (m, 2H) ppm. LC/MS:R_(t)=3.93 min, ES⁺ 435 (FA Waters).

Example 113((1S,2S,4R)-2-hydroxy-4-{[6-(1-naphthyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amino}cyclopentyl)methylsulfamate (Compound I-74) Step a:4-chloro-6-(1-naphthyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of N,N-diisopropylamine (265 μL, 1.89 mmol) in THF(3.00 mL) was added dropwise 1.60 M n-butyllithium in hexane (1.17 mL)at −78° C. under an atmosphere of Argon, and the mixture was stirred for20 minutes at −78° C. To this mixture was added dropwise a solution of4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.70mmol) in THF (5.00 mL), and the mixture was stirred for 1 h at −78° C. Asolution of zinc chloride (278 mg, 2.04 mmol) in THF (2.00 mL) was addeddropwise, and the resulting mixture was taken out the cooling bath andallowed to stir for 1 h. To a suspension oftetrakis(triphenylphosphine)palladium(0) (100 mg, 0.08 mmol) in THF(2.00 mL) was added 1-iodonaphthalene (0.30 mL, 2.06 mmol), and theresulting yellow solution was immediately added to the reaction mixture.The resulting mixture was heated at 80° C. for 1 h. After cooling to 23°C., the reaction mixture was quenched by the addition of water (70.0 mL)and the water layer was acidified with 1.00 M hydrochloric acid. Themixture was extracted with DCM (3×100 mL), and the organic layers werecombined. The organic layer was washed with brine, dried over MgSO₄,filtered, and evaporated under vacuum. The residue was purified viasilica gel column chromatography eluting with 30% ethyl acetate inhexanes to afford the title compound (665 mg, 82%). LC/MS: R_(t)=11.11min, ES⁺ 420.0 (FA long).

Step b: 4-chloro-6-(1-naphthyl)-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of4-chloro-6-(1-naphthyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine(350 mg, 0.73 mmol) in THF (2.50 mL) was added a solution of NaOH (205mg, 5.13 mmol) in methanol (1.19 mL), and the mixture was stirred for 15minutes. After quenching by addition of saturated NH₄Cl solution (80.0mL), the mixture was extracted with ethyl acetate (3×100 mL). Theorganic layers were combined, dried over MgSO₄, filtered, and evaporatedunder vacuum. The residue was dissolved in a small amount of methanol,and the suspension was filtered through a glass pad filter. The whitesolid was dried under high to afford the title compound (141 mg, 65%).

Step c:((1S,2S,4R)-2-hydroxy-4-{[6-(1-naphthyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amino}cyclopentyl)methylsulfamate (Compound I-74)

The title compound was prepared following the procedure described inExample 89 (steps c-e). ¹H-NMR (400 MHz, CD₃OD) δ: 8.31-8.25 (m, 1H),8.16 (s, 1H), 7.96-7.89 (m, 2H), 7.65 (dd, 1H, J=7.0, 0.8 Hz), 7.58-7.49(m, 3H), 6.91 (s, 1H), 4.92-4.80 (m, 1H), 4.45-4.39 (m, 1H), 4.35 (dd,1H, J=9.6, 7.5 Hz), 4.18 (dd, 1H, J=9.6, 7.3 Hz), 2.65-2.53 (m, 1H),2.34 (ddd, 1H, J=13.8, 7.5, 1.3 Hz), 2.21-2.11 (m, 1H), 2.00 (ddd, 1H,J=13.8, 7.0, 5.1 Hz), 1.87 (ddd, 1H, J=13.0, 8.6, 4.0 Hz). LC/MS:R_(t)=5.22 min, ES⁺ 454.1 (FA long).

Example 114{(1S,2S,4R)-2-hydroxy-4-[(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]cyclopentyl}methylsulfamate (Compound I-38)

The title compound was prepared following the procedure described inExample 113. ¹H NMR (400 MHz, CD₃OD) δ: 8.10 (s, 1H), 7.78-7.71 (m, 2H),7.45-7.38 (m, 2H), 7.33-7.26 (m, 1H), 6.93 (s, 1H), 4.86-4.79 (m, 1H),4.44-4.39 (m, 1H), 4.35 (dd, J=7.5, 9.5 Hz, 1H), 4.17 (dd, J=7.3, 9.8Hz, 1H), 2.64-2.52 (m, 1H), 2.36-2.27 (m, 1H), 2.19-2.08 (m, 1H),2.02-1.93 (m, 1H), 1.88-1.79 (m, 1H) ppm. LC/MS: R_(t)=4.02 min, ES⁺ 404(FA Waters).

Example 115((1S,2S,4R)-4-{[8-(7-chloroquinolin-4-yl)-7H-purin-6-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-73) Step a:6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

In DMF (4 mL, 0.05 mol) was suspended sodium hydride (47 mg, 0.0012 mol)at 0° C., to which was added a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol(0.200 g, 0.000554 mol) in 2.5 mL DMF. The mixture was stirred at 0° C.for 10 minutes and was added a solution of6-Chloro-9-(tetrahydropyranyl)purine (0.265 g, 0.00111 mol) (Example 33,step b) in 4 mL DMF. The reaction was stirred at 0° C. for 1 h andwarmed to 23° C. overnight. The reaction was quenched by addition ofsaturated aqueous NH₄Cl, and the mixture was extracted with ethylacetate, washed with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by flash chromatography (0 to 5%acetone/toluene) to obtain 271 mg (86.8%).

Step b:6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(288 mg, 0.000512 mol) in THF (10 mL, 0.1 mol) was addedN-Iodosuccinimide (0.576 g, 0.00256 mol), and the mixture was heated at70° C. overnight. The reaction was cooled, quenched by addition ofsaturated aqueous NaHSO₃ and the mixture was extracted with DCM (3×),washed with water, brine dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography (0 to 10% EtOAc/hexanes) toobtain 271 mg (76.9%). Reference: Nolsoe, J. M. J.; Gundersen, L-L.;Rise, F. Acta Chemica Scandinavica, 1999, 53, 366-372.

Step c:4-[6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl]-7-chloroquinoline

To a solution of6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(258.4 mg, 0.0003752 mol) in 1,2-Dimethoxyethane (3.0 mL, 0.029 mol) wasadded 7-chloroquinoline-4-boronic acid pinacol ester (0.158 g, 0.000546mol), barium hydroxide (0.228 g, 0.00133 mol), water (0.5 mL, 0.03 mol)and Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol), andthe mixture was heated at 90° C. overnight. The reaction was cooled,quenched by addition of water and the mixture was extracted with DCM(3×), washed with water, brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 30%EtOAc/hexanes) to obtain 180 mg (66.2%) mg. Reference: Cammidge, A. N.;Crepy, K. V. L. Tetrahedron, 2004, 60, 4377-4386.

Step d:((1S,2S,4R)-4-{[8-(7-chloroquinolin-4-yl)-7H-purin-6-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-73)

The title compound was prepared following the procedure described inExample 89 (steps d-e). ¹H NMR (CD₃OD, 400 MHz) δ: 9.05 (d, J=4.5 Hz,1H), 8.91 (d, J=9.1 Hz, 1H), 8.57 (s, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.92(d, J=4.5 Hz, 1H), 7.72 (dd, J=2.1, 9.1 Hz, 1H), 6.00-5.95 (m, 1H),4.48-4.45 (m, 1H), 4.37 (dd, J=7.6, 9.8 Hz, 1H), 4.21 (dd, J=7.3, 9.7Hz, 1H), 2.70-2.63 (m, 1H), 2.49-2.43 (m, 1H), 2.31-2.25 (m, 1H),2.21-2.17 (m, 2H) ppm. LC/MS: R_(t)=6.12 min, ES⁺ 490.98 (AA long).

Example 116((1S,2S,4R)-2-hydroxy-4-{[8-(1H-indol-3-yl)-7H-purin-6-yl]oxy}cyclopentyl)-methylsulfamate (Compound I-140)

The title compound was prepared following the procedure described inExample 115 using 1-(Phenylsulfonyl)indole-3-boronic acid pinacol ester.¹H NMR (CD₃OD, 400 MHz) δ: 8.41-8.33 (m, 2H), 8.08-8.03 (m, 1H),7.48-7.45 (m, 1H), 7.26-7.19 (m, 2H), 5.94-5.88 (m, 1H), 4.48-4.42 (m,1H), 4.38 (dd, J=7.3, 9.8 Hz, 1H), 4.21 (dd, J=7.0, 9.8 Hz, 1H),2.70-2.63 (m, 1H), 2.46-2.40 (m, 1H), 2.28-2.22 (m, 1H), 2.17-2.140 (m,2H) ppm. LC/MS: R_(t)=5.78 min, ES⁺ 445.04 (AA long).

Example 117[(1S,2S,4R)-4-({8-[4-(dimethylamino)-1-naphthyl]-7H-purin-6-yl}oxy)-2-hydroxycyclopentyl]methylsulfamate (Compound I-103)

The title compound was prepared following the procedure described inExample 115 usingN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-amine.¹H NMR (CD₃OD, 400 MHz) δ: 8.55-8.52 (m, 1H), 8.50 (s, 1H), 8.30-8.28(m, 1H), 7.80-7.77 (m, 1H), 7.55-7.53 (m, 2H), 7.20-7.17 (m, 1H),5.94-5.92 (m, 1H), 4.46-4.43 (m, 1H), 4.36 (dd, J=7.5, 9.8 Hz, 1H), 4.20(dd, J=7.3, 9.8 Hz, 1H), 2.95 (s, 6H), 2.66-2.60 (m, 1H), 2.46-2.39 (m,1H), 2.28-2.22 (m, 1H), 2.17 (m, 2H) ppm. LC/MS: R_(t)=6.75 min, ES⁺499.16 (AA long).

Example 118((1S,2S,4R)-4-{[8-(1-benzyl-1H-pyrazol-4-yl)-7H-purin-6-yl]oxy}-2-hydroxycyclopentyl)methylsulfamate (Compound I-129)

The title compound was prepared following the procedure described inExample 115 using 1-Benzylpyrazole-4-boronic acid pinacol ester. ¹H NMR(CD₃OD, 400 MHz) δ: 8.41 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.39-7.30(m, 5H), 5.90-5.85 (m, 1H), 5.43 (s, 2H), 4.46-4.43 (m, 1H), 4.36 (dd,J=7.6, 9.8 Hz, 1H), 4.19 (dd, J=7.2, 9.8 Hz, 1H), 2.66-2.60 (m, 1H),2.40-2.37 (m, 1H), 2.26-2.19 (m, 1H), 2.15-2.11 (m, 2H) ppm. LC/MS:R_(t)=5.72 min, ES⁺ 486.13 (AA long).

Example 119{(1S,2S,4R)-2-hydroxy-4-[(8-isoquinolin-4-yl-7H-purin-6-yl)oxy]cyclopentyl}-methylsulfamate (Compound I-112)

The title compound was prepared following the procedure described inExample 115 using 4-Isoquinolineboronic acid pinacol ester. ¹H NMR(CD₃OD, 400 MHz) δ: 9.41 (s, 1H), 8.87 (s, 1H), 8.74 (d, J=8.6 Hz, 1H),8.55 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.94 (m, 1H), 7.82 (m, 1H),5.98-5.96 (m, 1H), 4.49-4.46 (m, 1H), 4.37 (dd, J=7.5, 9.8 Hz, 1H), 4.20(dd, J=7.3, 9.7 Hz, 1H), 2.70-2.63 (m, 1H), 2.48-2.42 (m, 1H), 2.32-2.26(m, 1H), 2.20-2.16 (m, 2H) ppm. LC/MS: R_(t)=5.15 min, ES⁺ 457.08 (AAlong).

Example 120((1S,2S,4R)-2-hydroxy-4-{[8-(4-pyrrolidin-1-yl-1-naphthyl)-7H-purin-6-yl]-oxy}cyclopentyl)methylsulfamate (Compound I-139) Step a: 1-(4-bromo-1-naphthyl)pyrrolidine

To a solution of 1,4-dibromonaphthalene (500 mg, 0.002 mol), Pyrrolidine(0.18 mL, 0.0021 mol),(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.022 g, 0.000035mol), Sodium tert-butoxide (0.24 g, 0.0024 mol) in Toluene (5.00 mL,0.0469 mol) was added Tris(dibenzylideneacetone)dipalladium(0) (0.008 g,0.000009 mol), and the mixture was heated at 70° C. overnight. Thereaction was cooled, quenched by addition of water and the mixture wasextracted with DCM (3×), washed with water, brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography (0 to 25% hexanes/DCM) to obtain 400 mg (80%). Reference:Jean, L.; Rouden, J.; Maddaluno, J.; Lasne, M-C. J. Org. Chem. 2004, 69,8893-8902.

Step b:1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]pyrrolidine

To a solution of 1-(4-bromo-1-naphthyl)pyrrolidine (400 mg, 0.001 mol),bis(pinacolato)diboron (0.40 g, 0.0016 mol), potassium acetate (0.43 g,0.0043 mol) in N,N-Dimethylformamide (8 mL, 0.1 mol) was addedTetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.000043 mol), andthe mixture was heated at 100° C. overnight. The reaction was cooled,quenched by addition of water and the mixture was extracted with diethylether, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 25%DCM/hexanes) to obtain 221 mg (50%). Reference: Miyashita, K.; Sakai,T.; Imanishi, T. Org. Lett. 2003, 5, 2683-2686.

Step c:((1S,2S,4R)-2-hydroxy-4-{[8-(4-pyrrolidin-1-yl-1-naphthyl)-7H-purin-6-yl]oxy}-cyclopentyl)methylsulfamate (Compound I-139)

The title compound was prepared following the procedure described inExample 115 using1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]pyrrolidine.¹H NMR (CD₃OD, 400 MHz) δ: 8.58 (d, J=8.1 Hz, 1H), 8.48 (s, 1H), 8.31(d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.54-7.46 (m, 2H), 7.02 (d,J=8.2 Hz, 1H), 5.95-5.92 (m, 1H), 4.47-4.45 (m, 1H), 4.37 (dd, J=7.5,9.8 Hz, 1H), 4.20 (dd, J=7.2, 9.8 Hz, 1H), 3.5 (m, 4H), 2.70-2.62 (m,1H), 2.47-2.40 (m, 1H), 2.31-2.24 (m, 1H), 2.16 (dd, J=5.0, 9.0 Hz, 2H),2.07-2.04 (m, 4H) ppm. LC/MS: R_(t)=7.35 min, ES⁺ 525.26 (AA long).

Example 121[(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfanyl]-7H-purin-6-yl}-oxy)cyclopentyl]methylsulfamate (Compound I-136) Step a:6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentyl]oxy}-8-[(3-methylphenyl)sulfanyl]-9H-purine

To a solution of 3-methylbenzenethiol (0.55 mL, 0.0046 mol) in DMF (10mL, 0.2 mol) was added sodium hydride (0.093 g, 0.0023 mol). The mixturewas stirred at room temperature for 10 minutes and then6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(400 mg, 0.0006 mol) (Example 115, steps a-b) was added and the solutionwas heated at 150° C. for 8 hours. The reaction was cooled, quenched byaddition of water and the mixture was extracted with ethyl acetate,washed with water, brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography (0 to 30% ethylacetate/hexanes) to obtain 296 mg (80%) of the title compound.

Step b:[(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfanyl]-7H-purin-6-yl}-oxy)cyclopentyl]methylsulfamate (Compound I-136)

The title compound was prepared following the procedure described inExample 89 (steps d-e)¹H NMR (CD₃OD, 400 MHz) δ: 8.39 (s, 1H), 7.40-7.20(m, 4H), 5.84-5.82 (m, 1H), 4.40-4.39 (nm, 1H), 4.35-4.30 (m, 1H),4.17-4.13 (m, 1H), 2.57-2.52 (m, 1H), 2.39-2.33 (m, 1H), 2.33 (s, 3H),2.19-2.04 (m, 3H) ppm. LC/MS: R_(t)=6.35 min, ES+ 452.04 (AA long).

Example 122[(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfonyl]-9H-purin-6-yl}-oxy)cyclopentyl]methylsulfamate (Compound I-101)

To a solution of[(1S,2S,4R)-2-hydroxy-4-({8-[(3-methylphenyl)sulfanyl]-9H-purin-6-yl}oxy)cyclopentyl]methylsulfamate (13 mg, 0.000029 mol) in methanol (1.0 mL, 0.025 mol) at 0° C.was added a solution of Oxone® (0.0354 g, 0.0000576 mol) in water (0.5mL, 0.03 mol). The reaction was stirred for 4 hours at 0° C. and thenwarmed to 23° C. overnight. The reaction was partitioned with water andethyl acetate:isopropanol. The layers were separated and the aqueousextracted with ethyl acetate:isopropanol. The combined organics werewashed with water, brine, dried (Na₂SO₄), filtered, and collected invacuo. The residue was purified by flash chromatography (20% MeOH/DCM)to obtain 9 mg (60%). Reference: Ref.: Ramani R. Ranatunge, * et Al., J.Med. Chem., 2004, 47, 2180-2193. ¹H NMR (CD₃OD, 400 MHz) δ: 8.54 (s,1H), 7.94 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.52(dd, J=7.6, 13.3 Hz, 1H), 5.91-5.86 (m, 1H), 4.45-4.42 (m, 1H), 4.34(dd, J=7.5, 9.8 Hz, 1H), 4.18 (dd, J=7.3, 9.6 Hz, 1H), 2.65-2.59 (m,1H), 2.44 (s, 3H), 2.41-2.35 (m, 1H), 2.24-2.18 (m, 1H), 2.13-2.09 (m,2H) ppm. LC/MS: R_(t)=5.10 min, ES⁺ 484.11 (AA standard).

Example 123{(1S,2S,4R)-4-[(9-benzyl-9H-purin-6-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-80) Step a:5-Amino-4-benzylamino-6-chloropyrimidine

To a solution of 5-amino-4,6-dichloropyrimidine (8.4 g, 0.051 mol) in1-butanol (50.0 mL, 0.547 mol) was added triethylamine (12 mL, 0.084mol) and benzylamine (17 mL, 0.15 mol), and the mixture was heated at100° C. for 3 hours. The reaction was cooled at 0 C, filtered and washedwith ethanol. The residue was dissolved in CH₂Cl₂ and washed withsaturated aqueous NaHCO₃, and concentrated. The residue was trituratedin diethyl ether to obtain 11.5 g (96%) of a light brown solid.

Step b: 6-T Chloro-9-benzylpurine

To a solution of 4.0 M of hydrochloric acid in 1,4-dioxane (2.3 mL) inN,N-dimethylformamide (10.0 mL, 0.129 mol) was added ethyl orthoformate(2.00 mL, 0.0120 mol) and N⁴-benzyl-6-chloropyrimidine-4,5-diamine (500mg, 0.002 mol). The mixture was stirred for 3 days. The reaction wasquenched by addition of triethylamine (1.5 mL, 0.011 mol), extractedwith ethyl acetate, washed with saturated aqueous sodium bicarbonate,water, brine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (3 to 5% MeOH/DCM) to obtain 336 g(60%). LC/MS: R_(t)=1.49 min, ES⁺ 245.08 (AA standard).

Step c:{(1S,2S,4R)-4-[(9-benzyl-9H-purin-6-yl)oxy]-2-hydroxycyclopentyl}methylsulfamate (Compound I-80)

The title compound was prepared following the procedure described inExample 115 (steps a and d). ¹H NMR (CD₃OD, 400 MHz) δ: 8.51 (s, 1H),8.32 (s, 1H), 7.34-7.28 (m, 5H), 5.93-5.88 (m, 1H), 5.49 (s, 2H),4.46-4.43 (m, 1H), 4.35 (dd, J=7.5, 9.9 Hz, 1H), 4.18 (dd, J=7.1, 9.6Hz, 1H), 2.66-2.59 (m, 1H), 2.43-2.37 (m, 1H), 2.25-2.18 (m, 1H),2.14-2.10 (m, 2H) ppm. LC/MS: R_(t)=6.04 min, ES⁺ 420.11 (AA long).

Example 124((1S,2S,4R)-4-{[8-(2,3-dihydro-1-benzofuran-7-yl)-7H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-117)

The title compound was prepared following the procedure described inExample 89 using the appropriate carboxylic acid. ¹H NMR (CD₃OD, 400MHz) δ: 8.29-8.20 (m, 1H), 8.05-7.81 (m, 1H), 7.36 (dd, J=0.9, 7.3 Hz,1H), 7.01 (t, J=7.7 Hz, 1H), 4.86-4.78 (m, 3H), 4.44-4.41 (m, 1H), 4.36(dd, J=7.7, 9.6 Hz, 1H), 4.18 (dd, J=7.2, 9.8 Hz, 1H), 3.35-3.31 (m,2H), 2.63-2.55 (m, 1H), 2.38-2.32 (m, 1H), 2.20-2.12 (m, 1H), 1.99-1.92(m, 1H), 1.89-1.83 (m, 1H) ppm. LC/MS: R_(t)=5.75 min, ES⁺ 447.14 (AAlong).

Example 125{(1S,2S,4R)-2-hydroxy-4-[(8-quinolin-8-yl-7H-purin-6-yl)amino]cyclopentyl}-methylsulfamate (Compound I-84)

The title compound was prepared following the procedure described inExample 89 using the appropriate carboxylic acid. ¹H NMR (DMSO-d₆, 300MHz) δ: 9.22-9.12 (m, 1H), 8.93-8.76 (m, 1H), 8.62-8.54 (m, 1H),8.30-8.09 (m, 2H), 7.86-7.69 (m, 2H), 7.40-7.39 (m, 1H), 4.81-4.70 (m,1H), 4.30-4.19 (m, 2H), 4.08-3.98 (m, 1H), 2.48-2.42 (m, 1H), 2.28-2.20(m, 1H), 2.13-1.74 (m, 3H) ppm. LC/MS: R_(t)=6.00 min, ES⁺ 456.04 (AAlong).

Example 126[(1S,2S,4R)-4-({8-[4-(benzyloxy)phenyl]-7H-purin-6-yl}amino)-2-hydroxycyclopentyl]methylsulfamate (Compound I-102)

The title compound was prepared following the procedure described inExample 89 using the appropriate carboxylic acid. ¹H NMR (DMSO-d₆, 400MHz) δ: 8.15 (s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.46-7.30 (m, 5H), 7.15(d, J=8.8 Hz, 2H), 5.16 (s, 2H), 4.84-4.75 (m, 1H), 4.22-4.16 (m, 2H),4.00-3.97 (m, 1H), 2.48-2.42 (m, 1H), 2.12-1.69 (m, 4H) ppm. LC/MS:R_(t)=7.22 min, ES⁺ 511.06 (AA long).

Example 127((1S,2S,4R)-4-{[8-(2,3-dimethoxyphenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-67)

The title compound was prepared following the procedure described inExample 89 (steps a-d) using the appropriate carboxylic acid and Example1 (step d, using HCl for TBS deprotection). ¹H NMR (CD₃OD, 400 MHz) δ:8.30-8.23 (m, 1H), 7.87-7.61 (m, 1H), 7.25-7.18 (m, 2H), 4.92-4.80 (m,1H), 4.43-4.40 (m, 1H), 4.38-4.34 (m, 1H), 4.21-4.16 (m, 1H), 3.90 (d,6H), 2.63-2.54 (m, 1H), 2.40-2.31 (m, 1H), 2.20-2.12 (m, 1H), 2.00-1.91(m, 1H), 1.90-1.83 (m, 1H) ppm. LC/MS: R_(t)=5.92 min, ES⁺ 465 (AAlong).

Example 128((1S,2S,4R)-2-hydroxy-4-{methyl[8-(1-naphthyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-46) Step a:(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentylmethanesulfonate

To a solution of(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl-(dimethyl)silyl]oxy}methyl)cyclopentanol(2.02 g, 0.00560 mol) in CH₂Cl₂ (55.0 mL, 0.858 mol) at 0° C. was addedtriethylamine (1.8 mL, 0.013 mol) and methanesulfonyl chloride (0.650mL, 0.00840 mol) under an atmosphere of nitrogen. The mixture wasstirred at 0° C. for 30 minutes, and then warmed to 23° C. for 1 hour.The reaction was quenched by addition of saturated aqueous sodiumbicarbonate, extracted with DCM, dried (Na₂SO₄), filtered andconcentrated to give 2.66 g (100%).

Step b:[((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)methoxy](tert-butyl)dimethylsilane

To a solution of(1S,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentylmethanesulfonate (2.66 g, 0.00606 mol) in N,N-Dimethylformamide (20 mL,0.2 mol) was added sodium azide (1.21 g, 0.0186 mol), and the mixturewas heated at 55° C. for 3 hours. The reaction was cooled to 23° C.,quenched by addition of water and extracted with Et₂O (3×), washed withwater, brine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (0 to 15% ethyl acetate/hexane) toobtain 2.13 g (91.1%).

Step c:(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentanamine

A suspension of[((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl)methoxy](tert-butyl)dimethylsilane(2.13 g, 0.00552 mol) and 10% Pd/C (0.27 g, 0.00026 mol) in EtOAc (45.0mL, 0.461 mol) was stirred under an atmosphere of hydrogen overnight.The reaction was purged with nitrogen and filtered the mixture throughcelite with EtOAc. The filtrate was concentrated to obtain 1.83 g(92.1%) of the title compound.

Step d:Benzyl-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]carbamate

To a solution of(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine(0.098 g, 0.00027 mol) in Methylene chloride (2.0 mL, 0.031 mol) at 0°C. was added triethylamine (0.076 mL, 0.00054 mol) and benzylchloroformate (0.044 mL, 0.00031 mol). The reaction was warmed to 23° C.overnight. The reaction was quenched by addition of water₃ and themixture was extracted with methylene chloride (3×). The organic layerswere washed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography (0 to 8% EtOAc/hexanes) toobtain 73 mg (54%).

Step e:Benzyl-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]methylcarbamate

To a solution ofbenzyl-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]carbamate(0.073 g, 0.00015 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) wasadded sodium hydride (0.028 g, 0.0012 mol). The suspension was stirredfor 10 minutes and was added methyl iodide (0.023 mL, 0.00037 mol)(purified on alumina) and the mixture was stirred overnight. Thereaction was quenched by addition of saturated aqueous ammonium chlorideand the mixture was extracted with ethyl acetate, washed with brine,dried (Na₂SO₄), filtered and concentrated.

Step f:(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-N-methylcyclopentanamine

A suspension ofbenzyl-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]methylcarbamate(0.394 g, 0.000776 mol) and 10% Pd/C (0.04 g, 0.00004 mol) in ethanol(5.0 mL) was stirred under an atmosphere of hydrogen overnight. Thereaction was purged with nitrogen and filtered the mixture throughcelite with ethanol. The filtrate was concentrated to obtain 0.290 g(99%).

Step g:((1S,2S,4R)-2-hydroxy-4-{methyl[8-(1-naphthyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-46)

The title compound was prepared following the procedures described inExample 89 (steps c-d) and Example 1 (step d, using HCl for TBSdeprotection). ¹H NMR (CD₃OD, 400 MHz) δ: 8.95 (d, J=7.5 Hz, 1H), 8.23(s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.97-7.92 (m, 2H), 7.63-7.54 (m, 3H),6.58-6.44 (m, 1H), 4.43-4.41 (m, 1H), 4.35 (dd, J=7.8, 9.7 Hz, 1H), 4.19(dd, J=7.5, 9.5 Hz, 1H), 3.38 (s, 3H), 2.68-2.60 (m, 1H), 2.20-1.97 (m,4H) ppm. LC/MS: R_(t)=1.49 min, ES⁻ 467.16 (AA standard).

Example 129((1S,2S,4R)-2-hydroxy-4-{[8-(2-methylphenyl)-9H-purin-6-yl]amino}-cyclopentyl)methylsulfamate (Compound I-107)

The title compound was prepared following the procedure described inExample 89 using the appropriate carboxylic acid. ¹H NMR (CD₃OD, 400MHz) δ: 8.23 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.44-7.32 (m, 3H),4.43-4.40 (m, 1H), 4.34 (dd, J=7.5, 9.8 Hz, 1H), 4.17 (dd, J=7.3, 9.8Hz, 1H), 2.61-2.53 (m, 1H), 2.53 (s, 3H), 2.37-2.31 (m, 1H), 2.20-2.12(m, 1H), 1.99-1.92 (m, 1H), 1.89-1.82 (m, 1H) ppm. LC/MS: R_(t)=1.27min, ES⁺ 419.20 (AA standard).

Example 130{(1S,2S,4R)-2-hydroxy-4-[methyl(9-methyl-8-phenyl-9H-purin-6-yl)-amino]cyclopentyl}methylsulfamate (Compound I-123) Step a: 6-Chloro-9-methyl-8-phenyl-9H-purine

To a solution of 6-chloro-8-phenyl-7H-purine (0.200 g, 0.000867 mol)(Example 109, step a) in DMF (8.0 mL, 0.10 mol) was added sodium hydride(0.025 g, 0.0010 mol). The mixture was stirred for 20 minutes and tothis was added methyl iodide (0.065 mL, 0.0010 mol) and the mixture wasstirred for 2 hours. The reaction was quenched by addition of saturatedaqueous NH₄Cl, and the mixture was extracted with ethyl acetate, washedwith water, brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by flash chromatography (3 to 10% acetone/toluene)to obtain 145 mg (68%).

Step b:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-9-methyl-8-phenyl-9H-purin-6-amine

The title compound was prepared following the procedure described inExample 89 (step c).

Step c:N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclopentyl]-N,9-dimethyl-8-phenyl-9H-purin-6-amine

To a solution ofN-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-9-methyl-8-phenyl-9H-purin-6-amine(200 mg, 0.0004 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) was addedsodium hydride (0.112 g, 0.00280 mol). The mixture was stirred for 30minutes and to this was added methyl iodide (0.05 mL, 0.0008 mol) andthe mixture was stirred overnight. The reaction was quenched by additionof saturated aqueous NH₄Cl, and the mixture was extracted with ethylacetate, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (0 to 10%MeOH/DCM) to obtain 200 mg (100%).

Step d:{(1S,2S,4R)-2-hydroxy-4-[methyl(9-methyl-8-phenyl-9H-purin-6-yl)amino]-cyclopentyl}methylsulfamate (Compound I-123)

The title compound was prepared following the procedure described inExample 89 (steps d-e). ¹H NMR (CD₃OD, 400 MHz) δ: 8.24 (s, 1H),7.84-7.80 (m, 2H), 7.57-7.52 (m, 3H), 6.44-6.36 (m, 1H), 4.40-4.38 (m,1H), 4.33 (dd, J=7.7, 9.8 Hz, 1H), 4.17 (dd, J=7.3, 9.8 Hz, 1H), 3.83(s, 3H), 3.34 (s, 3H), 2.63-2.56 (m, 1H), 2.16-1.92 (m, 4H) ppm. LC/MS:R_(t)=1.41 min, ES⁺ 433 (AA standard).

Example 131{(1S,2S,4R)-2-hydroxy-4-[(9-methyl-8-phenyl-9H-purin-6-yl)-amino]cyclopentyl}methylsulfamate (Compound I-130)

The title compound was prepared following the procedures described inExample 130 (step a) and Example 89 (steps c-e). ¹H NMR (CD₃OD, 400 MHz)δ: 8.28 (s, 1H), 7.82-7.80 (m, 2H), 7.60-7.58 (m, 3H), 4.87-4.86 (m,1H), 4.42-4.39 (m, 1H), 4.36-4.31 (m, 1H), 4.18-4.14 (m, 1H), 3.85 (s,3H), 2.59-2.54 (m, 1H), 2.36-2.30 (m, 1H), 2.19-2.11 (m, 1H), 2.00-1.91(m, 1H), 1.87-1.80 (m, 1H) ppm. LC/MS: R_(t)=1.30 min, ES⁻ 417 (AAstandard).

Example 132{(1S,2S,4R)-2-hydroxy-4-[(7-methyl-8-phenyl-7H-purin-6-yl)-amino]cyclopentyl}methylsulfamate (Compound I-36) Step a:N-(4,6-dichloropyrimidin-5-yl)benzamide

A mixture of 5-amino-4,6-dichloropyrimidine (1.15 g, 0.00701 mol) andbenzoyl chloride (1.0 mL, 0.0086 mol) was heated at 100° C. overnight.The reaction was cooled and the residue was triturated with diethylether, filtered and collected to obtain 1.6 g (85%).

Step b: N-(4,6-dichloropyrimidin-5-yl)-N-methylbenzamide

To a solution of N-(4,6-dichloropyrimidin-5-yl)benzamide (3.0 g, 0.011mol) in tetrahydrofuran (70 mL, 0.9 mol) was added cesium carbonate (9.8g, 0.030 mol). The suspension was stirred for 5 minutes and to this wasadded methyl iodide (1.4 mL, 0.022 mol) (purified on aluminum oxide).After stirring for 1 hour, cesium carbonate (5.0 g, 0.015 mol) andmethyl iodide (0.70 mL, 0.011 mol) (purified on alumina) were added. Thereaction was stirred for 2 hours, quenched by addition of saturatedaqueous NH₄Cl, and the mixture was extracted with ethyl acetate, washedwith water, brine, dried (Na₂SO₄), filtered, concentrated andtrituration in diethyl ether to obtain 2.54 g (80%).

Step c: N-(4-amino-6-chloropyrimidin-5-yl)-N-methylbenzamide

To a solution of N-(4,6-dichloropyrimidin-5-yl)-N-methylbenzamide (0.455g, 0.00161 mol) in 1-butanol (5 mL, 0.05 mol) was added ammoniumhydroxide (0.50 mL, 0.013 mol) and the mixture was refluxed for 24 h. Tothe reaction was added ammonium hydroxide (1.0 mL, 0.026 mol) and themixture was refluxed for 24 h, cooled, extracted with a mixture of ethylacetate:isopropanol, washed with saturated aqueous sodium bicarbonate,brine, dried (Na₂SO₄), filtered, concentrated and triturated in diethylether to obtain 284 mg (67.1%).

Step d: 6-Chloro-7-methyl-8-phenyl-7H-purine

A suspension of N-(4-amino-6-chloropyrimidin-5-yl)-N-methylbenzamide(0.285 g, 0.00108 mol) in phosphoryl chloride (8 mL, 0.08 mol) washeated at 115° C. overnight. The mixture was cooled, concentrated andtriturated in diethyl ether to obtain 224 mg (84.4%) yellow solid.LC/MS: R_(t)=1.30 min, ES⁺ 245.08 (AA standard).

Step e:{(1S,2S,4R)-2-hydroxy-4-[(7-methyl-8-phenyl-7H-purin-6-yl)amino]cyclopentyl}-methylsulfamate (Compound I-36)

The title compound was prepared following the procedure described inExample 89 (steps c-e). ¹H NMR (CD₃OD, 400 MHz) δ: 8.32 (s, 1H),7.77-7.73 (m, 2H), 7.61-7.57 (m, 3H), 4.98-4.91 (m, 1H), 4.42-4.39 (m,1H), 4.34 (dd, J=7.8, 9.5 Hz, 1H), 4.16 (dd, J=7.3, 9.9 Hz, 1H), 4.06(s, 3H), 2.66-2.59 (m, 1H), 2.37-2.31 (m, 1H), 2.21-2.12 (m, 1H),2.03-1.96 (m, 1H), 1.92-1.85 (m, 1H) ppm. LC/MS: R_(t)=1.12 min, ES⁺419.13 (AA standard).

Example 133((1S,2S,4R)-4-{[8-(2-chlorophenyl)-9H-purin-6-yl]amino}-2-hydroxycyclopentyl)methylsulfamate (Compound I-34)

The title compound was prepared following the procedures described inExample 89 (steps a, c-d), Example 109 (step a), and Example 1 (step d,using TBAF for TBS group deprotection). ¹H NMR (CD₃OD, 400 MHz) δ: 8.25(s, 1H), 7.82-7.88 (m, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.55-7.47 (m, 2H),4.42-4.41 (m, 1H), 4.35 (dd, J=7.7, 9.6 Hz, 1H), 4.17 (dd, J=7.5, 9.6Hz, 1H), 2.61-2.55 (m, 1H), 2.37-2.32 (m, 1H), 2.20-2.12 (m, 1H),1.99-1.92 (m, 1H), 1.89-1.82 (m, 1H) ppm. LC/MS: R_(t)=4.35 min, ES⁺ 439(FA long).

Example 134{(1S,2S,4R)-2-hydroxy-4-[(8-phenyl-9H-purin-6-yl)oxy]cyclopentyl}methylsulfamate (Compound I-63) Step a:9-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]oxy}-8-phenyl-9H-purine

The title compound was prepared following the procedures described inExample 123 (step a), Example 109 (step a), and Example 115 (step a).

Step b:{(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(8-phenyl-9H-purin-6-yl)-oxy]cyclopentyl}methanol

A suspension of9-benzyl-6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-phenyl-9H-purine(0.161 g, 0.000249 mol), 10% Pd/C (0.04 g, 0.00004 mol) and formic acid(0.1 mL, 0.003 mol) in methanol (11.0 mL, 0.272 mol) was stirred underan atmosphere of nitrogen overnight. Added formic acid (0.2 mL, 0.005mol) and 10% Pd/C (0.04 g, 0.00004 mol) to the reaction and stirred 24h. Added 10% Pd/C (0.060 g, 0.000056 mol) and formic acid (0.2 mL, 0.005mol) to the reaction and stirred an additional 24 h. The reaction waspurged with nitrogen and filtered the mixture through celite with DCM.The filtrate was concentrated, purified by flash chromatography (30 to50% ethyl acetate/hexane) to obtain 30 mg (27%). LC/MS: R_(t)=2.08 min,ES⁺ 441.18 (AA standard).

Step c:{(1S,2S,4R)-2-hydroxy-4-[(8-phenyl-9H-purin-6-yl)oxy]cyclopentyl}methylsulfamate (Compound I-63)

The title compound was prepared following the procedure described inExample 89 (step e). ¹H NMR (CD₃OD, 400 MHz) δ: 8.47 (s, 1H), 8.16-8.11(m, 2H), 7.57-7.54 (m, 3H), 5.94-5.90 (m, 1H), 4.49-4.45 (m, 1H), 4.37(dd, J=7.5, 9.5 Hz, 1H), 4.20 (dd, J=7.5, 9.6 Hz, 1H), 2.70-2.64 (m,1H), 2.46-2.40 (m, 1H), 2.30-2.24 (m, 1H), 2.18-2.14 (m, 2H) ppm. LC/MS:R_(t)=1.15 min, ES⁺ 406.11 (AA standard).

Example 135{(1S,2S,4R)-2-hydroxy-4-[(2-phenyl[1,3]oxazolo[5,4-d]pyrimidin-7-yl)-amino]cyclopentyl}methylsulfamate (Compound I-90) Step a:7-Chloro-2-phenyl[1,3]oxazolo[5,4-d]pyrimidine

A mixture of 5-amino-4,6-dichloropyrimidine (1.05 g, 0.00640 mol) andbenzoyl chloride (0.89 mL, 0.0077 mol) was subjected to microwaveirradiation (100° C.) for 2 hours. The reaction was cooled and theresidue was triturated with diethyl ether, filtered and collected toobtain 1.15 g (77.5%) of a yellow solid. LC/MS: R_(t)=1.84 min, ES⁺232.19 (AA standard).

Step c:{(1S,2S,4R)-2-hydroxy-4-[(2-phenyl[1,3]oxazolo[5,4-d]pyrimidin-7-yl)-amino]cyclopentyl}methylsulfamate (Compound I-90)

The title compound was prepared following the procedures described inExample 89 (steps c-d) and Example 1 (step d, using TBAF for the TBSgroup deprotection). ¹H NMR (CD₃OD, 400 MHz) δ: 8.28 (s, 1H), 8.19-8.16(m, 2H), 7.58-7.53 (m, 3H), 4.89-4.86 (m, 1H), 4.43-4.40 (m, 1H), 4.34(dd, J=7.8, 9.5 Hz, 1H), 4.17 (dd, J=7.3, 9.6 Hz, 1H), 2.64-2.55 (m,1H), 2.35-2.27 (m, 1H), 2.18-2.09 (m, 1H), 2.01-1.95 (m, 1H), 1.89-1.83(m, 1H) ppm. LC/MS: R_(t)=1.44 min, ES⁺ 406.31 (AA standard).

Example 136 Enzyme Preparation

All protein accession numbers provided herein refer to the EntrezProtein database maintained by the National Center for BiotechnologyInformation (NCBI), Bethesda, Md.

Generation of E1 Enzymes

Following manufacturer instructions, baculoviruses were generated withthe Bac-to-Bac Expression System (Invitrogen) for the followingproteins: untagged NAEα (APPBP1; NP_(—)003896.1), N-terminallyHis-tagged NAEβ (UBE1C; NP_(—)003959.3), untagged SAEα (SAE1;NP_(—)005491.1), N-terminally His-tagged SAEβ (UBA2; NP_(—)005490.1),N-terminally His-tagged murine UAE (UBE1X; NP_(—)033483). NAEα/His-NAEβand SAEα/His-SAEβ complexes were generated by co-infection of Sf9 cells,which were harvested after 48 hours. His-mUAE was generated by singleinfection of Sf9 cells and harvested after 72 hours. Expressed proteinswere purified by affinity chromatography (Ni-NTA agarose, Qiagen) usingstandard buffers.

Generation of E2 Enzymes

Ubc12 (UBE2M; NP_(—)003960.1), Ubc9 (UBE2I; NP_(—)003336.1), Ubc2(UBE2A; NP_(—)003327.2) were subcloned into pGEX (Pharmacia) andexpressed as N-terminally GST tagged fusion proteins in E. coli.Expressed proteins were purified by conventional affinity chromatographyusing standard buffers.

Generation of Ubl Proteins

Nedd8 (NP_(—)006147), Sumo-1 (NP_(—)003343) and Ubiquitin (withoptimized codons) were subcloned into pFLAG-2 (Sigma) and expressed asN-terminally Flag tagged fusion proteins in E. coli. Expressed proteinswere purified by conventional chromatography using standard buffers.

Example 137 E1 Enzyme Assays Nedd8-Activating Enzyme (NAE) HTRF Assay.

The NAE enzymatic reaction totaled 50 μL and contained 50 mM HEPES (pH7.5), 0.05% BSA, 5 mM MgCl₂, 20 M ATP, 250 μM GSH, 0.01 M Ubc12-GST,0.075 μM Nedd8-Flag and 0.20 nM recombinant human NAE enzyme. Theenzymatic reaction mixture, with and without compound inhibitor, wasincubated at room temperature 24° C. for 105 minutes in a 384-well platebefore termination with 25 μL of Stop/Detection buffer (0.1M HEPES pH7.5, 0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptatelabeled monoclonal anti-FLAG M2 antibody (CisBio International) and8.125 μg/mL PHYCOLINK goat anti-GST allophycocyanin (XL-APC) antibody(Prozyme)). After incubation for 1 hour at 24° C., quantification of theFRET was performed on the Analyst™ HT 96.384 (Molecular Devices).

Compounds I-1 to I-153 were tested in this assay. Compounds I-1, I-2,I-3, I-5, I-6, I-8 to I-12, I-14, I-15, I-17, I-18, I-19, I-21, I-24 toI-27, I-29, I-32, I-34, I-37 to I-43, I-45, I-46, I-47, I-49, I-55,I-56, I-60, I-62 to I-65, I-67, I-68, I-69, I-71, I-73, I-74, I-82,I-83, I-84, I-87, I-88, I-90, I-93, I-99, I-100, I-101, I-102, I-103m,I-105 to I-109, I-111, I-112, I-115, I-117, I-118, I-121, I-122, I-124,I-125, I-126, I-128 to I-131, I-133, I-134, I-136, I-137, I-139, I-140,I-142, I-143, I-146, I-147, I-150, I-151, and I-153 exhibited IC₅₀values less than or equal to 500 nM in this assay. Compounds I-4, I-7,I-16, I-28, I-33, I-35, I-36, I-48, I-53, I-54, I-59, I-66, I-77, I-79,I-80, I-81, I-86, I-92, I-94, I-96, I-98, I-110, I-113, I-114, I-119,I-120, I-123, I-127, I-132, I-138, I-141, I-148, I-149, and I-152exhibited IC₅₀ values greater than 500 nM and less than 10 M in thisassay. Compounds I-13, I-20, I-22, I-23, I-30, I-31, I-58, I-61, I-76,I-85, I-89, I-97, I-144, and I-145 exhibited IC₅₀ values greater than 10μM in this assay.

Sumo-Activating Enzyme (SAE) HTRF Assay.

The SAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.01 μM Ubc9-GSTand 0.125 μM Sumo-Flag respectively and the concentration of ATP was 0.5μM. Recombinant human SAE (0.11 nM) was the source of enzyme.

Ubiquitin-Activating Enzyme (UAE) HTRF Assay.

The UAE enzymatic reaction was conducted as outlined above for NAEexcept that Ubc12-GST and Nedd8-Flag were replaced by 0.005 μM Ubc2-GSTand 0.125 μM Ubiquitin-Flag respectively and the concentration of ATPwas 0.1 μM. Recombinant mouse UAE (0.3 nM) was the source of enzyme.

Example 138 Cellular Assays Anti-Proliferation Assay (WST)

Calu-6 (2400/well) or other tumor cells in 80 μL of appropriate cellculture medium (MEM for Calu6, Invitrogen) supplemented with 10% fetalbovine serum (Invitrogen) was seeded in wells of a 96-well cell cultureplate and incubated for 24 hours in a tissue culture incubator. Compoundinhibitors were added in 20 μL culture media to the wells and the plateswas incubated for 72 hours at 37° C. 10% final concentration of WST-1reagent (Roche) was added to each well and incubated for 3.5 hours (forCalu6) at 37° C. The optical density for each well was read at 450 nmusing a spectrophotometer (Molecular Devices). Percent inhibition wascalculated using the values from a DMSO control set to 100% viability.

Anti-Proliferation Assay (ATPLite)

Calu-6 (1500 cells/well) or other tumor cells were seeded in 72 μL ofappropriate cell culture medium (MEM for Calu6, Invitrogen) supplementedwith 10% fetal bovine serum (Invitrogen) in wells of a 384-wellPoly-D-Lysine coated cell culture plate. Compound inhibitors were addedin 8 μL 10% DMSO/PBS to the wells and the plates were incubated for 72hours at 37° C. Cell culture medium was aspirated, leaving 25 μL in eachwell. 25 μL of ATPlite 1step™ reagent (Perkin Elmer) was added to eachwell. The luminescence for each well was read using the LeadSeekerMicroplate Reader (Molecular Devices). Percent inhibition was calculatedusing the values from a DMSO control set to 100% viability.

Example 139 In vivo Assays In Vivo Tumor Efficacy Model

Calu6 (5×10⁶ cells), HCT116 (2×10⁶ cells) or other tumor cells in 100 μLphosphate buffered saline were aseptically injected into thesubcutaneous space in the right dorsal flank of female Ncr nude mice(age 5-8 weeks, Charles River) using a 26-gauge needle. Beginning on day7 after inoculation, tumors were measured twice weekly using a verniercaliper. Tumor volumes were calculated using standard procedures(0.5×(length×width²)). When the tumors reached a volume of approximately200 mm³ mice were randomized into groups and injected intravenously inthe tail vein with compound inhibitor (100 μL) at various doses andschedules. Alternatively, compound inhibitor may be delivered to mice byintraperitoneal or subcutaneous injection or oral administration. Allcontrol groups received vehicle alone. Tumor size and body weight wasmeasured twice a week and the study terminated when the control tumorsreached approximately 2000 mm³.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

While a number of embodiments of this invention have been described, itis apparent that the provided basic examples may be altered to conveyother embodiments, which utilize the compounds and methods of thisinvention. It will thus be appreciated that the scope of this inventionhas been represented herein by way of example and is not intended to belimited by the specific embodiments, rather is defined by the appendedclaims.

1-3. (canceled)
 4. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein: D is —C(R^(h))═;E is —C(R^(h))═; R⁹ is hydrogen, halo, cyano, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵,—CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; andeach R^(h) independently is hydrogen, halo, —CN—, —OR⁵, —N(R⁴)₂, —SR⁶,or an optionally substituted C₁₋₄ aliphatic group; W is —CH₂—, —CHF—,—CF₂—, —CH(R¹)—, —CF(R¹)—, —NH—, —N(R¹)—, —O—, —S—, or —NHC(O)—; R¹ isC₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic; X is —CH₂—, —CHF—, —CF₂—, —NH—,or —O—; Y is —O—, —S—, or —C(R^(m))(R^(n))—; R^(a) is hydrogen, fluoro,—CN, —N, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵, —C(O)N(R⁴)₂, —C(O)R⁵,—OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with one or two substituentsindependently selected from —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c) together form a bond; R^(b)is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic; R^(c) ishydrogen, fluoro, —CN, —N, —OR⁵, —N(R⁴)₂, —NR⁴CO₂R⁶, —NR⁴C(O)R⁵,—C(O)N(R⁴)₂, —C(O)R⁵, —OC(O)N(R⁴)₂, —OC(O)R⁵, —OCO₂R⁶, or a C₁₋₄aliphatic or C₁₋₄ fluoroaliphatic optionally substituted with one or twosubstituents independently selected from —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); or R^(a) and R^(c) together forma bond; R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄fluoroaliphatic; R^(e) is hydrogen, or C₁₋₄ aliphatic; or R^(e), takentogether with one R^(f) and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; or R^(e), taken together with R^(m) and theintervening carbon atoms, forms a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; R^(e′) is hydrogen or C₁₋₄aliphatic; or R^(e′), taken together with R^(m) and the interveningcarbon atoms, forms a fused cyclopropane ring, which is optionallysubstituted with one or two substituents independently selected fromfluoro or C₁₋₄ aliphatic; each R^(f) is independently hydrogen, fluoro,C₁₋₄ aliphatic or C₁₋₄ fluoroaliphatic; or two R^(f) taken together form═O; or two R^(f), taken together with the carbon atom to which they areattached, form a 3- to 6-membered carbocyclic ring; or one R^(f), takentogether with R^(e) and the intervening carbon atoms, forms a 3- to6-membered spirocyclic ring; R^(m) is hydrogen, fluoro, —N(R⁴)₂, or anoptionally substituted C₁₋₄ aliphatic group; or R^(m) and R^(n) togetherform ═O or ═C(R⁵)₂; or R^(m) and R^(e), taken together with theintervening carbon atoms, form a fused cyclopropane ring, which isoptionally substituted with one or two substituents independentlyselected from fluoro or C₁₋₄ aliphatic; or R^(m) and R^(e′), takentogether with the intervening carbon atoms, form a fused cyclopropanering, which is optionally substituted with one or two substituentsindependently selected from fluoro or C₁₋₄ aliphatic; R^(n) is hydrogen,fluoro, or an optionally substituted C₁₋₄ aliphatic group; or R^(m) andR^(n) together form ═O or ═C(R⁵)₂; each R⁴ independently is hydrogen oran optionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; or two R⁴ on the same nitrogen atom, taken together with thenitrogen atom, form an optionally substituted 4- to 8-memberedheterocyclyl ring having, in addition to the nitrogen atom, 0-2 ringheteroatoms independently selected from N, O, and S; R^(4x) is hydrogen,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portionof which may be optionally substituted; R^(4y) is hydrogen, C₁₋₄ alkyl,C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of which may beoptionally substituted, or an optionally substituted 5- or 6-memberedaryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y), takentogether with the nitrogen atom to which they are attached, form anoptionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R⁵ independently is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; each R^(5x) independently is hydrogen, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl or C₆₋₁₀ar(C₁₋₄)alkyl; each R⁶ independently is an optionally substitutedaliphatic, aryl, or heteroaryl group; and m is 1, 2, or
 3. 5. Thecompound of claim 4, wherein: R^(g) is hydrogen, C₁₋₆ aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(1g), —R^(2g), -T¹-R^(1g), -T¹-R^(2g),—V¹-T¹-R^(1g), —V¹-T¹-R^(2g), —V¹—R^(1g), or -T¹-V¹—R^(1g); T¹ is a C₁₋₆alkylene chain substituted with 0-2 independently selected R^(3a) orR^(3b), wherein the alkylene chain optionally is interrupted by—C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)—C(═NR⁴)—,—N(R⁴)CO₂—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —OC(O)—, —OC(O)N(R⁴)—, —C(O)—,—CO₂—, —C(O)N(R⁴)—, —C(═NR⁴)—N(R⁴)—, —C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or—C(R⁶)═N—O—, and wherein T¹ or a portion thereof optionally forms partof a 3-7 membered ring; V¹ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—,—S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,—N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)C(═NR⁴)—, —N(R⁴)CO₂—, —N(R⁴)SO₂—,—N(R⁴)SO₂N(R⁴)—, —OC(O)—, —OC(O)N(R⁴)—, —C(O)—, —CO₂—, —C(O)N(R⁴)—,—C(O)N(R⁴)—O—, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)—, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)—,—C(═NR⁴)—N(R⁴)—, —C(NR⁴)═N(R⁴)—, —C(═NR⁴)—O—, or —C(R⁶)═N—O—; eachR^(1g) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2g) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R′)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, or—C(R⁶)═N—OR⁵; each R^(3a) independently is —F, —OH, —O(C₁₋₄ alkyl), —CN,—N(R⁴)₂, —C(O)(C₁₋₄ alkyl)-, —CO₂H, —CO₂(C₁₋₄ alkyl), —C(O)NH₂, or—C(O)NH(C₁₋₄ alkyl); each R^(3b) independently is a C₁₋₃ aliphaticoptionally substituted with R^(3a) or R⁷, or two substituents R^(3b) onthe same carbon atom, taken together with the carbon atom to which theyare attached, form a 3- to 6-membered cycloaliphatic ring; and each R⁷independently is an optionally substituted aryl or heteroaryl ring. 6.The compound of claim 5, characterized by formula (III):

or a pharmaceutically acceptable salt thereof, wherein: Q is -T¹- or—V¹-T¹-; V¹ is —N(R⁸)—, —O—, or —S—; R⁸ is hydrogen or C₁₋₄ aliphatic;T¹ is a C₁₋₄ alkylene chain optionally substituted with one or twogroups independently selected from fluoro, C₁₋₄ aliphatic, and C₁₋₄fluoroaliphatic; and Ring C is a 3- to 8-membered heterocyclyl orcycloaliphatic ring, or a 5- or 6-membered aryl or heteroaryl ring, anyof which rings is substituted with 0-2 R^(o) and 0-2 R^(8o); each R^(o)independently is halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵, —OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵,—C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionally substitutedaliphatic, or an optionally substituted aryl, heterocyclyl, orheteroaryl group; or two R^(o) on the same saturated ring carbon atom,taken together with the carbon atom, form an optionally substituted 3-to 8-membered spirocyclic cycloaliphatic or heterocyclyl ring; or twoadjacent R^(o), taken together with the intervening ring atoms, form anoptionally substituted fused 4- to 8-membered aromatic or non-aromaticring having 0-3 ring heteroatoms selected from the group consisting ofO, N, and S; each R^(8o) independently is C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, halo, —OR^(5x), —N(R^(4x))(R^(4y)), or a C₁₋₄ aliphaticor C₁₋₄ fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); R^(4x) ishydrogen, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or C₆₋₁₀ ar(C₁₋₄)alkyl, the arylportion of which may be optionally substituted; R^(4y) is hydrogen, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, C₆₋₁₀ ar(C₁₋₄)alkyl, the aryl portion of whichmay be optionally substituted, or an optionally substituted 5- or6-membered aryl, heteroaryl, or heterocyclyl ring; or R^(4x) and R^(4y),taken together with the nitrogen atom to which they are attached, forman optionally substituted 4- to 8-membered heterocyclyl ring having, inaddition to the nitrogen atom, 0-2 ring heteroatoms independentlyselected from N, O, and S; and each R^(5x) independently is hydrogen,C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, or an optionally substituted C₆₋₁₀ aryl orC₆₋₁₀ ar(C₁₋₄)alkyl.
 7. The compound of claim 6, wherein Ring C is aC₃₋₆ cycloaliphatic, phenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or tetrahydropyrimidinylring, any of which is substituted with 0-2 R^(o) and 0-2 R^(8o).
 8. Thecompound of claim 6, wherein Ring C is a C₃₋₆ cycloaliphatic, phenyl,oxazolyl, or isoxazolyl ring, any of which is substituted with 0-2R^(8o) and optionally is fused to an optionally substituted benzene,dioxolane, or dioxane ring.
 9. The compound of claim 5, characterized byformula (IV):

or a pharmaceutically acceptable salt thereof, wherein: V¹ is —N(R⁸)—,—O—, or —S—; R⁸ is hydrogen or C₁₋₄ aliphatic; and Ring D is anoptionally substituted mono- or bicyclic ring system.
 10. The compoundof claim 9, wherein Ring D is furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,benzofuranyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, quinuclidinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, phenanthridinyl,tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, chromanyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, bicycloheptanyl or bicyclooctanyl, any of which groupsis optionally substituted.
 11. The compound of claim 10, wherein: eachsubstitutable saturated ring carbon atom in Ring D is unsubstituted orsubstituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(p); each substitutable unsaturatedring carbon atom in Ring D is unsubstituted or substituted with —R^(p);each substitutable ring nitrogen atom in Ring D is unsubstituted orsubstituted with —R^(9p); each R^(p) independently is halo, —NO₂, —CN,—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,—N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, —C(R⁶)═N—OR⁵, or an optionallysubstituted aliphatic, or an optionally substituted aryl, heterocyclyl,or heteroaryl group; or two R^(p) on the same saturated carbon atom,taken together with the carbon atom to which they are attached, form anoptionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring;and each R^(9p) independently is —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionally substituted with R³ or R⁷.12. The compound of claim 11, wherein: each R^(p) independently is halo,C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, —R^(1p), —R^(2p), -T²-R^(1p), or-T²-R^(2p); or two R^(p) on the same saturated carbon atom, takentogether with the carbon atom to which they are attached, form anoptionally substituted 3- to 6-membered spirocyclic cycloaliphatic ring;T² is a C₁₋₆ alkylene chain substituted with 0-2 independently selectedR^(3a) or R^(3b); each R^(1p) independently is an optionally substitutedaryl, heteroaryl, or heterocyclyl group; and each R^(2p) independentlyis —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —SR⁵, —S(O)R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—R⁶, —NR⁴CO₂R⁶, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —O—C(O)R⁵,—OCO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —CO₂R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)—OR⁵,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(═NR⁴)—N(R⁴)—OR⁵, or —C(R⁶)═N—OR⁵.
 13. The compound ofclaim 12, wherein Ring D is an optionally substituted indanyl,tetrahydronaphthyl, or chromanyl.
 14. The compound of claim 12, wherein:V¹ is —N(R⁸)—; Ring D is:

each R^(p) independently is halo, —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)), or is a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); each R^(8p)independently is fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or is a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); or two R^(8p) on the same carbon atom togetherform ═O or ═C(R^(5x))₂; provided that when two R^(8p) are attached tothe same carbon atom, one must be selected from the group consisting offluoro, —CO₂R^(5x), —C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); and furtherprovided that R^(8p) is other than —OR^(5x) or —N(R^(4x))(R^(4y)) whenlocated at a position adjacent to a ring oxygen atom; s is 0, 1, 2, 3,or 4; and t is 0, 1, or
 2. 15. The compound of claim 5, wherein: R^(g)is —N(R⁸)(R⁹); R⁸ is hydrogen or C₁₋₄ aliphatic; R⁹ is hydrogen, C₁₋₄aliphatic, -T³-R^(9a) or -T⁴-R^(9b); T³ is a C₁₋₆ alkylene chainsubstituted with 0-2 independently selected R^(3a) or R^(3b); T⁴ is aC₂₋₆ alkylene chain substituted with 0-2 independently selected R^(3a)or R^(3b); R^(9a) is —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —S(O)R⁶, —SO₂R⁶,—SO₂—N(R⁴)₂, —C(R⁵)═N—OR⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(═NR⁴)—N(R⁴)₂, or —C(═NR⁴)—OR⁵; and R^(9b) is halo, —NO₂, —CN, —OR⁵,—SR⁶, —N(R⁴)₂, —N(R⁴)C(O)R⁵, —N(R⁴)C(O)N(R⁴)₂, —N(R⁴)CO₂R⁵, —O—CO₂—R⁵,—OC(O)N(R⁴)₂, —OC(O)R⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)S(O)₂R⁶, or—N(R⁴)SO₂—N(R⁴)₂.
 16. The compound of claim 15, wherein R⁹ is hydrogenor a C₁₋₆ aliphatic or C₁₋₆ fluoroaliphatic optionally substituted withone or two substituents independently selected from of —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)). 17-22.(canceled)
 23. The compound of claim 4, characterized by formula (IX-A):

or a pharmaceutically acceptable salt thereof, wherein stereochemicalconfigurations at asterisked positions indicate absolute configuration;each R^(p) independently is halo, —OR^(5x), —N(R^(4x))(R^(4y)),—CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)), or is a C₁₋₄ aliphatic or C₁₋₄fluoroaliphatic optionally substituted with —OR^(5x),—N(R^(4x))(R^(4y)), —CO₂R^(5x), or —C(O)N(R^(4x))(R^(4y)); each R^(8p)independently is fluoro, —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)), or is a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —CO₂R^(5x), or—C(O)N(R^(4x))(R^(4y)); or two R^(8p) on the same carbon atom togetherform ═O or ═C(R^(5x))₂; provided that when two R^(8p) are attached tothe same carbon atom, one must be selected from fluoro, —CO₂R^(5x),—C(O)N(R^(4x))(R^(4y)), or a C₁₋₄ aliphatic or C₁₋₄ fluoroaliphaticoptionally substituted with —OR^(5x), —N(R^(4x))(R^(4y)), —COR^(5x), or—C(O)N(R^(4x))(R^(4y)); and further provided that R^(8p) is other than—OR^(5x) or —N(R^(4x))(R^(4y)) when located at a position adjacent to aring oxygen atom; s is 0, 1, 2, 3, or 4; and t is 0, 1, or
 2. 24. Apharmaceutical composition, comprising a compound of claim 4 and apharmaceutically acceptable carrier.
 25. The pharmaceutical compositionof claim 24, formulated for administration to a human patient.
 26. Amethod of decreasing an E1 enzyme activity in a sample, comprisingcontacting the sample with a compound of claim
 4. 27-30. (canceled) 31.A method for treating an immune response disorder or vascular cellproliferation disorder in a patient in need thereof, comprisingadministering to the patient a compound of claim
 4. 32. The compound ofclaim 4, wherein W is —CH₂—, —CHF—, —CF₂—, —NH—, —O—, —S—, or —NHC(O)—.33. The compound of claim 4, characterized by one or more of thefollowing features: (a) X is —O—; (b) Y is —CH₂—; (c) W is —NH— (d)R^(a) is —OH; (e) R^(b) and R^(d) are each independently hydrogen orC₁₋₄ aliphatic; (f) R^(c) is hydrogen, fluoro, or —OR⁵; (g) R^(e) andR^(e′) are each hydrogen; (h) each R^(f) is hydrogen; and (i) m is 1.34. The compound of claim 4, which is I-16[(1R,2R,3S,4R)-2,3-dihydroxy-4-[(pyridin-3-ylcarbonyl)amino]cyclopentyl)-methylsulfamate; I-23[(1R,2R,3S,4R)-2,3-dihydroxy-4-[(pyridin-2-ylcarbonyl)amino]cyclopentyl)-methylsulfamate; I-35[(1S,2S,4R)-4-[(2-([(1S)-5-chloro-3,3-dimethyl-2,3-dihydro-IH-inden-1-yl]amino]pyridin-4-yl)oxy]-2-hydroxycyclopentyl]methylsulfamate; I-94[(1S,2S,4R)-4-([2-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyridin-4-yl]oxy)-2-hydroxycyclopentyl]methylsulfamate; I-144[(1R,2R,3S,4R)-4-[(2-([(1S)-2,3-dihydro-1H-inden-1-ylamino]carbonyl)pyridin-4-yl)amino]-2,3-dihydroxycyclopentyl)methylsulfamate; I-145((1R,2R,3S,4R)-4-([2-(2,3-dihydro-1H-indol-1-ylcarbonyl)pyridin-4-yl]amino)-2,3-dihydroxycyclopentyl)methylsulfamate; or a pharmaceutically acceptable salt thereof.